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Yang J, Yao Y, Fan S, Li X. USP9X PROMOTES LPS-INDUCED FIBROBLAST CELL APOPTOSIS, INFLAMMATION, AND OXIDATIVE STRESS BY REGULATION OF TBL1XR1 DEUBIQUITINATION. Shock 2025; 63:210-216. [PMID: 39841820 DOI: 10.1097/shk.0000000000002442] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/24/2025]
Abstract
ABSTRACT Background: Ubiquitination and deubiquitination are involved in the progression of human diseases, including acute pneumonia. In this study, we aimed to explore the functions of ubiquitin-specific peptidase 9X-linked (USP9X) in lipopolysaccharide (LPS)-treated WI-38 cells. Methods: WI-38 cells were treated with LPS to induce the cellular damage and inflammation. 3-(4, 5-Dimethyl-2-thiazolyl)-2, 5-diphenyl-2-H-tetrazolium bromide (MTT) assay, and 5-ethynyl-2'-deoxyuridine (EdU) assay were performed to examine the proliferation of LPS-treated WI-38 cells. Flow cytometry analysis was conducted to detect LPS-treated WI-38 cell apoptosis. ELISA kits were utilized to determine the concentrations of inflammatory factors (IL-1β and TNF-α). Superoxide dismutase activity and reactive oxygen species level were examined with related kits. Ubibrowser (http://ubibrowser.bio-it.cn/ubibrowser/), ubiquitination assay, and co-immunoprecipitation assay demonstrated the interaction between USP9X and transducin β-like 1X related protein 1 (TBL1XR1). qRT-PCR assay and western blot assay were manipulated to determine the expression of USP9X and TBL1XR1. TBL1XR1 and USP9X knockdown experiments were conducted to explore their functions on LPS-induced WI-38 cell injury and inflammation. Results: TBL1XR1 expression was upregulated in LPS-treated WI-38 cells. TBL1XR1 knockdown promoted cell proliferation and repressed apoptosis, inflammation, and oxidative stress in LPS-treated WI-38 cells. Moreover, USP9X deubiquitinated TBL1XR1 to regulate TBL1XR1 expression. USP9X knockdown restored the effects of LPS on WI-38 cell proliferation, apoptosis, inflammation, and oxidative stress, but these effects of USP9X knockdown were further abolished by TBL1XR1 overexpression. In addition, USP9X promoted the NF-κB signaling pathway by the deubiquitination of TBL1XR1. Conclusion: USP9X promoted the apoptosis, inflammation, and oxidative stress of LPS-stimulated WI-38 cells through the deubiquitination of TBL1XR1.
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Affiliation(s)
- Juan Yang
- Department of Respiratory and Critical Care Medicine, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, China
| | - Yingying Yao
- Department of Respiratory and Critical Care Medicine, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, China
| | - Shuo Fan
- Department of Emergency and Intensive Care, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, China
| | - Xiaoyan Li
- Department of Respiratory and Critical Care Medicine, Xiangyang Central Hospital, Affiliated Hospital of Hubei University of Arts and Science, Xiangyang, Hubei, China
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2
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Dong J, Sathyan K, Scott T, Mukherjee R, Guertin M. ZNF143 binds DNA and stimulates transcription initiation to activate and repress direct target genes. Nucleic Acids Res 2025; 53:gkae1182. [PMID: 39676670 PMCID: PMC11754675 DOI: 10.1093/nar/gkae1182] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/29/2024] [Revised: 09/30/2024] [Accepted: 11/20/2024] [Indexed: 12/17/2024] Open
Abstract
Transcription factors bind to sequence motifs and act as activators or repressors. Transcription factors interface with a constellation of accessory cofactors to regulate distinct mechanistic steps to regulate transcription. We rapidly degraded the essential and pervasively expressed transcription factor ZNF143 to determine its function in the transcription cycle. ZNF143 facilitates RNA polymerase initiation and activates gene expression. ZNF143 binds the promoter of nearly all its activated target genes. ZNF143 also binds near the site of genic transcription initiation to directly repress a subset of genes. Although ZNF143 stimulates initiation at ZNF143-repressed genes (i.e. those that increase transcription upon ZNF143 depletion), the molecular context of binding leads to cis repression. ZNF143 competes with other more efficient activators for promoter access, physically occludes transcription initiation sites and promoter-proximal sequence elements, and acts as a molecular roadblock to RNA polymerases during early elongation. The term context specific is often invoked to describe transcription factors that have both activation and repression functions. We define the context and molecular mechanisms of ZNF143-mediated cis activation and repression.
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Affiliation(s)
- Jinhong Dong
- Center for Cell Analysis and Modeling, University of Connecticut, 400 Farmington Ave, Farmington, Connecticut 06030, USA
| | - Kizhakke Mattada Sathyan
- Center for Cell Analysis and Modeling, University of Connecticut, 400 Farmington Ave, Farmington, Connecticut 06030, USA
| | - Thomas G Scott
- Department of Biochemistry and Molecular Genetics, University of Virginia, 1340 Jefferson Park Ave, Charlottesville, Virginia 22903, USA
| | - Rudradeep Mukherjee
- Center for Cell Analysis and Modeling, University of Connecticut, 400 Farmington Ave, Farmington, Connecticut 06030, USA
| | - Michael J Guertin
- Center for Cell Analysis and Modeling, University of Connecticut, 400 Farmington Ave, Farmington, Connecticut 06030, USA
- Department of Genetics and Genome Sciences, University of Connecticut, 400 Farmington Ave, Farmington, Connecticut 06030, USA
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3
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Ritter MJ, Amano I, Hollenberg AN. Transcriptional Cofactors for Thyroid Hormone Receptors. Endocrinology 2025; 166:bqae164. [PMID: 39679543 PMCID: PMC11702866 DOI: 10.1210/endocr/bqae164] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/30/2024] [Revised: 12/06/2024] [Accepted: 12/13/2024] [Indexed: 12/17/2024]
Abstract
Thyroid hormone (TH) is essential throughout life. Its actions are mediated primarily by the thyroid hormone receptor (THR), which is a nuclear receptor. Classically, the THRs act as inducible transcription factors. In the absence of TH, a corepressor complex is recruited to the THR to limit TH-related gene expression. In the presence of TH, the corepressor complex is dismissed and a coactivator complex is recruited to facilitate TH-related gene expression. These coregulators can interact with multiple nuclear receptors and are also key in maintaining normal physiologic function. The nuclear receptor corepressor 1 (NCOR1) and the nuclear receptor corepressor 2 (NCOR2) have been the most extensively studied corepressors of the THR involved in histone deacetylation. The steroid receptor coactivator/p160 (SRC) family and in particular, SRC-1, plays a key role in histone acetylation associated with the THR. The Mediator Complex is also required for pretranscription machinery assembly. This mini-review focuses on how these transcriptional cofactors influence TH-action and signaling, primarily via histone modifications.
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Affiliation(s)
- Megan J Ritter
- Section of Endocrinology, Diabetes, Nutrition and Weight Management, Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA
| | - Izuki Amano
- Section of Endocrinology, Diabetes, Nutrition and Weight Management, Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA
- Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi 371-8511, Japan
| | - Anthony N Hollenberg
- Section of Endocrinology, Diabetes, Nutrition and Weight Management, Department of Medicine, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA
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4
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Gui Z, Shi W, Zhou F, Yan Y, Li Y, Xu Y. The role of estrogen receptors in intracellular estrogen signaling pathways, an overview. J Steroid Biochem Mol Biol 2025; 245:106632. [PMID: 39551163 DOI: 10.1016/j.jsbmb.2024.106632] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/01/2024] [Revised: 10/29/2024] [Accepted: 11/09/2024] [Indexed: 11/19/2024]
Abstract
To date five members of estrogen receptors (ESRs) have been reported. They are grouped into two classes, the nuclear estrogen receptors are members of the nuclear receptor family which found at nuclear, cytoplasm and plasma membrane, and the membrane estrogen receptors, such as G protein-coupled estrogen receptor 1, ESR-X and Gq-coupled membrane estrogen receptor. The structure and function of estrogen receptors, and interaction between ESR and coregulators were reviewed. In canonical pathway ESRs can translocate to the nucleus, bind to the target gene promotor with or without estrogen responsive element and regulate transcription, mediating the genomic effects of estrogen. Coactivators and corepressors are recruited to activate or inhibit transcription by activated ESRs. Many coactivators and corepressors are recruited to activate or inhibit ESR mediated gene transcription via different mechanisms. ESRs also indirectly bind to the promoter via interaction with other transcription factors, tethering the transcription factors. ESRs can be phosphorylated by several kinases such as p38, extracellular-signal-regulated kinase, and activated protein kinase B, and which activates transcription without ligand binding. Non-genomic estrogen action can be manifested by the increases of cytoplasmic NO and Ca2+ through the activation of membrane ESRs. In female, ESRs signaling is crucial for folliculogenesis, oocyte growth, ovulation, oviduct and uterus. In male, ESRs signaling modulates libido, erectile function, leydig cell steroidogenesis, sertoli cell's function, and epididymal fluid homeostatsis, supporting spermatogenesis and sperm maturation. The abnormal ESRs signaling is believed to be closely related to reproductive diseases and cancer.
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Affiliation(s)
- Zichang Gui
- College of Physical Education and Health, East China Normal University, Shanghai 200241, China.
| | - Wei Shi
- School of Chemistry, Biology and Environment, Yuxi Normal University, Yuxi 653100, China.
| | - Fangting Zhou
- School of Chemistry, Biology and Environment, Yuxi Normal University, Yuxi 653100, China.
| | - Yongqing Yan
- Yunnan Dasheng Biotechnology Co., LTD, Yuxi 653100, China.
| | - Yuntian Li
- School of Chemistry, Biology and Environment, Yuxi Normal University, Yuxi 653100, China.
| | - Yang Xu
- School of Chemistry, Biology and Environment, Yuxi Normal University, Yuxi 653100, China; Yunnan Dasheng Biotechnology Co., LTD, Yuxi 653100, China.
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5
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Simsek YK, Tofil HP, Rosenthal MI, Evans RM, Danielski CL, Beasley KE, Alsayed H, Shapira ME, Strauss RI, Wang M, Roggero VR, Allison LA. Nuclear receptor corepressor 1 levels differentially impact the intracellular dynamics of mutant thyroid hormone receptors associated with resistance to thyroid hormone syndrome. Mol Cell Endocrinol 2024; 594:112373. [PMID: 39299378 PMCID: PMC11531384 DOI: 10.1016/j.mce.2024.112373] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/10/2024] [Revised: 09/05/2024] [Accepted: 09/16/2024] [Indexed: 09/22/2024]
Abstract
Thyroid hormone receptor α1 (TRα1) undergoes nucleocytoplasmic shuttling and mediates gene expression in response to thyroid hormone (T3). In Resistance to Thyroid Hormone Syndrome α (RTHα), certain TRα1 mutants have higher affinity for nuclear corepressor 1 (NCoR1) and may form stable complexes that are not released in the presence of T3. Here, we examined whether NCoR1 modulates intranuclear mobility and nuclear retention of TRα1 or RTHα-associated mutants in transfected human cells, as a way of analyzing critical structural components of TRα1 and to further explore the correlation between mutations in TRα1 and aberrant intracellular trafficking. We found no significant difference in intranuclear mobility, as measured by fluorescence recovery after photobleaching, between TRα1 and select RTHα mutants, irrespective of NCoR1 expression. Nuclear-to-cytoplasmic fluorescence ratios of RTHα mutants, however, varied from TRα1 when NCoR1 was overexpressed, with a significant increase in nuclear retention for A263V and a significant decrease for A263S and R384H. In NCoR1-knockout cells, nuclear retention of A263S, A263V, P389R, A382P, C392X, and F397fs406X was significantly decreased compared to control (wild-type) cells. Luciferase reporter gene transcription mediated by TRα1 was significantly repressed by both NCoR1 overexpression and NCoR1 knockout. Most RTHα mutants showed minimal induction regardless of NCoR1 levels, but T3-mediated transcriptional activity was decreased for R384C and F397fs406X when NCoR1 was overexpressed, and also decreased for N359Y in NCoR1-knockout cells. Our results suggest a complex interaction between NCoR1 and RTHα mutants characterized by aberrant intracellular localization patterns and transcriptional activity that potentially arise from variable repressor complex stability, and may provide insight into RTHα pathogenesis on a molecular and cellular level.
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Affiliation(s)
- Yigit K Simsek
- Department of Biology, William & Mary, 540 Landrum Drive, Integrated Science Center 3030, Williamsburg, VA, 23185, USA
| | - H Page Tofil
- Department of Biology, William & Mary, 540 Landrum Drive, Integrated Science Center 3030, Williamsburg, VA, 23185, USA
| | - Matthew I Rosenthal
- Department of Biology, William & Mary, 540 Landrum Drive, Integrated Science Center 3030, Williamsburg, VA, 23185, USA
| | - Rochelle M Evans
- Department of Biology, William & Mary, 540 Landrum Drive, Integrated Science Center 3030, Williamsburg, VA, 23185, USA
| | - Caroline L Danielski
- Department of Biology, William & Mary, 540 Landrum Drive, Integrated Science Center 3030, Williamsburg, VA, 23185, USA
| | - Katelyn E Beasley
- Department of Biology, William & Mary, 540 Landrum Drive, Integrated Science Center 3030, Williamsburg, VA, 23185, USA
| | - Haytham Alsayed
- Department of Biology, William & Mary, 540 Landrum Drive, Integrated Science Center 3030, Williamsburg, VA, 23185, USA
| | - Molly E Shapira
- Department of Biology, William & Mary, 540 Landrum Drive, Integrated Science Center 3030, Williamsburg, VA, 23185, USA
| | - Rebecca I Strauss
- Department of Biology, William & Mary, 540 Landrum Drive, Integrated Science Center 3030, Williamsburg, VA, 23185, USA
| | - Moyao Wang
- Department of Biology, William & Mary, 540 Landrum Drive, Integrated Science Center 3030, Williamsburg, VA, 23185, USA
| | - Vincent R Roggero
- Department of Biology, William & Mary, 540 Landrum Drive, Integrated Science Center 3030, Williamsburg, VA, 23185, USA
| | - Lizabeth A Allison
- Department of Biology, William & Mary, 540 Landrum Drive, Integrated Science Center 3030, Williamsburg, VA, 23185, USA.
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Eiers AK, Vettorazzi S, Tuckermann JP. Journey through discovery of 75 years glucocorticoids: evolution of our knowledge of glucocorticoid receptor mechanisms in rheumatic diseases. Ann Rheum Dis 2024; 83:1603-1613. [PMID: 39107081 DOI: 10.1136/ard-2023-225371] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/05/2024] [Accepted: 07/20/2024] [Indexed: 08/09/2024]
Abstract
For three-quarters of a century, glucocorticoids (GCs) have been used to treat rheumatic and autoimmune diseases. Over these 75 years, our understanding of GCs binding to nuclear receptors, mainly the glucocorticoid receptor (GR) and their molecular mechanisms has changed dramatically. Initially, in the late 1950s, GCs were considered important regulators of energy metabolism. By the 1970s/1980s, they were characterised as ligands for hormone-inducible transcription factors that regulate many aspects of cell biology and physiology. More recently, their impact on cellular metabolism has been rediscovered. Our understanding of cell-type-specific GC actions and the crosstalk between various immune and stromal cells in arthritis models has evolved by investigating conditional GR mutant mice using the Cre/LoxP system. A major achievement in studying the complex, cell-type-specific interplay is the recent advent of omics technologies at single-cell resolution, which will provide further unprecedented insights into the cell types and factors mediating GC responses. Alongside gene-encoded factors, anti-inflammatory metabolites that participate in resolving inflammation by GCs during arthritis are just being uncovered. The translation of this knowledge into therapeutic concepts will help tackle inflammatory diseases and reduce side effects. In this review, we describe major milestones in preclinical research that led to our current understanding of GC and GR action 75 years after the first use of GCs in arthritis.
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Affiliation(s)
- Ann-Kathrin Eiers
- Institute of Comparative Molecular Endocrinology, Ulm University, Ulm, Baden-Württemberg, Germany
| | - Sabine Vettorazzi
- Institute of Comparative Molecular Endocrinology, Ulm University, Ulm, Baden-Württemberg, Germany
| | - Jan P Tuckermann
- Institute of Comparative Molecular Endocrinology, Ulm University, Ulm, Baden-Württemberg, Germany
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7
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Stolz V, de Freitas e Silva R, Rica R, Zhu C, Preglej T, Hamminger P, Hainberger D, Alteneder M, Müller L, Waldherr M, Waltenberger D, Hladik A, Agerer B, Schuster M, Frey T, Krausgruber T, Knapp S, Campbell C, Schmetterer K, Trauner M, Bergthaler A, Bock C, Boucheron N, Ellmeier W. Nuclear receptor corepressor 1 controls regulatory T cell subset differentiation and effector function. eLife 2024; 13:e78738. [PMID: 39466314 PMCID: PMC11517256 DOI: 10.7554/elife.78738] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Accepted: 09/25/2024] [Indexed: 10/29/2024] Open
Abstract
FOXP3+ regulatory T cells (Treg cells) are key for immune homeostasis. Here, we reveal that nuclear receptor corepressor 1 (NCOR1) controls naïve and effector Treg cell states. Upon NCOR1 deletion in T cells, effector Treg cell frequencies were elevated in mice and in in vitro-generated human Treg cells. NCOR1-deficient Treg cells failed to protect mice from severe weight loss and intestinal inflammation associated with CD4+ T cell transfer colitis, indicating impaired suppressive function. NCOR1 controls the transcriptional integrity of Treg cells, since effector gene signatures were already upregulated in naïve NCOR1-deficient Treg cells while effector NCOR1-deficient Treg cells failed to repress genes associated with naïve Treg cells. Moreover, genes related to cholesterol homeostasis including targets of liver X receptor (LXR) were dysregulated in NCOR1-deficient Treg cells. However, genetic ablation of LXRβ in T cells did not revert the effects of NCOR1 deficiency, indicating that NCOR1 controls naïve and effector Treg cell subset composition independent from its ability to repress LXRβ-induced gene expression. Thus, our study reveals that NCOR1 maintains naïve and effector Treg cell states via regulating their transcriptional integrity. We also reveal a critical role for this epigenetic regulator in supporting the suppressive functions of Treg cells in vivo.
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Affiliation(s)
- Valentina Stolz
- Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of ImmunologyViennaAustria
| | - Rafael de Freitas e Silva
- Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of ImmunologyViennaAustria
| | - Ramona Rica
- Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of ImmunologyViennaAustria
| | - Ci Zhu
- Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of ImmunologyViennaAustria
| | - Teresa Preglej
- Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of ImmunologyViennaAustria
| | - Patricia Hamminger
- Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of ImmunologyViennaAustria
| | - Daniela Hainberger
- Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of ImmunologyViennaAustria
| | - Marlis Alteneder
- Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of ImmunologyViennaAustria
| | - Lena Müller
- Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of ImmunologyViennaAustria
| | - Monika Waldherr
- Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of ImmunologyViennaAustria
| | - Darina Waltenberger
- Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of ImmunologyViennaAustria
| | - Anastasiya Hladik
- Medical University of Vienna, Vienna, Department of Medicine I, Laboratory of Infection BiologyViennaAustria
| | - Benedikt Agerer
- CeMM Research Centre for Molecular Medicine of the Austrian Academy of SciencesViennaAustria
| | - Michael Schuster
- CeMM Research Centre for Molecular Medicine of the Austrian Academy of SciencesViennaAustria
| | - Tobias Frey
- Medical University of Vienna, Department of Laboratory MedicineViennaAustria
| | - Thomas Krausgruber
- CeMM Research Centre for Molecular Medicine of the Austrian Academy of SciencesViennaAustria
- Medical University of Vienna, Center for Medical Statistics, Informatics, and Intelligent Systems, Institute of Artificial IntelligenceViennaAustria
| | - Sylvia Knapp
- Medical University of Vienna, Vienna, Department of Medicine I, Laboratory of Infection BiologyViennaAustria
| | - Clarissa Campbell
- CeMM Research Centre for Molecular Medicine of the Austrian Academy of SciencesViennaAustria
| | - Klaus Schmetterer
- Medical University of Vienna, Department of Laboratory MedicineViennaAustria
| | - Michael Trauner
- Medical University of Vienna, Department of Internal Medicine III, Division of Gastroenterology and Hepatology, Hans Popper Laboratory of Molecular HepatologyViennaAustria
| | - Andreas Bergthaler
- CeMM Research Centre for Molecular Medicine of the Austrian Academy of SciencesViennaAustria
- Medical University of Vienna, Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute for Hygiene and Applied ImmunologyViennaAustria
| | - Christoph Bock
- CeMM Research Centre for Molecular Medicine of the Austrian Academy of SciencesViennaAustria
- Medical University of Vienna, Center for Medical Statistics, Informatics, and Intelligent Systems, Institute of Artificial IntelligenceViennaAustria
| | - Nicole Boucheron
- Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of ImmunologyViennaAustria
| | - Wilfried Ellmeier
- Medical University of Vienna, Center for Pathophysiology, Infectiology and Immunology, Institute of ImmunologyViennaAustria
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Bale R, Doshi G. Deciphering the role of siRNA in anxiety and depression. Eur J Pharmacol 2024; 981:176868. [PMID: 39128805 DOI: 10.1016/j.ejphar.2024.176868] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/04/2024] [Revised: 07/02/2024] [Accepted: 08/05/2024] [Indexed: 08/13/2024]
Abstract
Anxiety and depression are central nervous system illnesses that are among the most prevalent medical concerns of the twenty-first century. Patients with this condition and their families bear psychological, financial, and societal hardship. There are currently restrictions when utilizing the conventional course of treatment. RNA interference is expected to become an essential approach in anxiety and depression due to its potent and targeted gene silencing. Silencing of genes by post-transcriptional modification is the mechanism of action of small interfering RNA (siRNA). The suppression of genes linked to disease is typically accomplished by siRNA molecules in an efficient and targeted manner. Unfavourable immune responses, off-target effects, naked siRNA instability, nuclease vulnerability, and the requirement to create an appropriate delivery method are some of the challenges facing the clinical application of siRNA. This review focuses on the use of siRNA in the treatment of anxiety and depression.
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Affiliation(s)
- Rajeshwari Bale
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V L M Road, Vile Parle (w), Mumbai, 400056, India
| | - Gaurav Doshi
- Department of Pharmacology, SVKM's Dr. Bhanuben Nanavati College of Pharmacy, V L M Road, Vile Parle (w), Mumbai, 400056, India.
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Zhu X, Cheng SY. Thyroid Hormone Receptors as Tumor Suppressors in Cancer. Endocrinology 2024; 165:bqae115. [PMID: 39226152 PMCID: PMC11406550 DOI: 10.1210/endocr/bqae115] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/21/2024] [Revised: 08/21/2024] [Accepted: 09/02/2024] [Indexed: 09/05/2024]
Abstract
Accumulated research has revealed the multifaceted roles of thyroid hormone receptors (TRs) as potent tumor suppressors across various cancer types. This review explores the intricate mechanisms underlying TR-mediated tumor suppression, drawing insights from preclinical mouse models and cancer biology. This review examines the tumor-suppressive functions of TRs, particularly TRβ, in various cancers using preclinical models, revealing their ability to inhibit tumor initiation, progression, and metastasis. Molecular mechanisms underlying TR-mediated tumor suppression are discussed, including interactions with oncogenic signaling pathways like PI3K-AKT, JAK-STAT, and transforming growth factor β. Additionally, this paper examines TRs' effect on cancer stem cell activity and differentiation, showcasing their modulation of key cellular processes associated with tumor progression and therapeutic resistance. Insights from preclinical studies underscore the therapeutic potential of targeting TRs to impede cancer stemness and promote cancer cell differentiation, paving the way for precision medicine in cancer treatment and emphasizing the potential of TR-targeted therapies as promising approaches for treating cancers and improving patient outcomes.
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Affiliation(s)
- Xuguang Zhu
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
| | - Sheue-yann Cheng
- Laboratory of Molecular Biology, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, 20892, USA
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10
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Chen Y, Anderson MT, Payne N, Santori FR, Ivanova NB. Nuclear Receptors and the Hidden Language of the Metabolome. Cells 2024; 13:1284. [PMID: 39120315 PMCID: PMC11311682 DOI: 10.3390/cells13151284] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 06/12/2024] [Revised: 07/16/2024] [Accepted: 07/22/2024] [Indexed: 08/10/2024] Open
Abstract
Nuclear hormone receptors (NHRs) are a family of ligand-regulated transcription factors that control key aspects of development and physiology. The regulation of NHRs by ligands derived from metabolism or diet makes them excellent pharmacological targets, and the mechanistic understanding of how NHRs interact with their ligands to regulate downstream gene networks, along with the identification of ligands for orphan NHRs, could enable innovative approaches for cellular engineering, disease modeling and regenerative medicine. We review recent discoveries in the identification of physiologic ligands for NHRs. We propose new models of ligand-receptor co-evolution, the emergence of hormonal function and models of regulation of NHR specificity and activity via one-ligand and two-ligand models as well as feedback loops. Lastly, we discuss limitations on the processes for the identification of physiologic NHR ligands and emerging new methodologies that could be used to identify the natural ligands for the remaining 17 orphan NHRs in the human genome.
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Affiliation(s)
- Yujie Chen
- Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA; (Y.C.); (M.T.A.); (N.P.)
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA
| | - Matthew Tom Anderson
- Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA; (Y.C.); (M.T.A.); (N.P.)
| | - Nathaniel Payne
- Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA; (Y.C.); (M.T.A.); (N.P.)
| | - Fabio R. Santori
- Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA; (Y.C.); (M.T.A.); (N.P.)
| | - Natalia B. Ivanova
- Center for Molecular Medicine, University of Georgia, Athens, GA 30602, USA; (Y.C.); (M.T.A.); (N.P.)
- Department of Biochemistry and Molecular Biology, University of Georgia, Athens, GA 30602, USA
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11
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Ritter MJ, Amano I, van der Spek AH, Gower AC, Undeutsch HJ, Rodrigues VAP, Daniel HE, Hollenberg AN. Nuclear Receptor Corepressors NCOR1 and SMRT Regulate Metabolism via Intestinal Regulation of Carbohydrate Transport. Endocrinology 2024; 165:bqae100. [PMID: 39106294 PMCID: PMC11337007 DOI: 10.1210/endocr/bqae100] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/27/2024] [Revised: 07/29/2024] [Accepted: 08/01/2024] [Indexed: 08/09/2024]
Abstract
Nuclear receptor action is mediated in part by the nuclear receptor corepressor 1 (NCOR1) and the silencing mediator of retinoic acid and thyroid hormone receptor (SMRT). NCOR1 and SMRT regulate metabolic pathways that govern body mass, insulin sensitivity, and energy expenditure, representing an understudied area in the realm of metabolic health and disease. Previously, we found that NCOR1 and SMRT are essential for maintaining metabolic homeostasis and their knockout (KO) leads to rapid weight loss and hypoglycemia, which is not survivable. Because of a potential defect in glucose absorption, we sought to determine the role of NCOR1 and SMRT specifically in intestinal epithelial cells (IECs). We used a postnatal strategy to disrupt NCOR1 and SMRT throughout IECs in adult mice. These mice were characterized metabolically and underwent metabolic phenotyping, body composition analysis, and glucose tolerance testing. Jejunal IECs were isolated and profiled by bulk RNA sequencing. We found that the postnatal KO of NCOR1 and SMRT from IECs leads to rapid weight loss and hypoglycemia with a significant reduction in survival. This was accompanied by alterations in glucose metabolism and activation of fatty acid oxidation in IECs. Metabolic phenotyping confirmed a reduction in body mass driven by a loss of body fat without altered food intake. This appeared to be mediated by a reduction of key intestinal carbohydrate transporters, including SGLT1, GLUT2, and GLUT5. Intestinal NCOR1 and SMRT act in tandem to regulate glucose levels and body weight. This in part may be mediated by regulation of intestinal carbohydrate transporters.
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Affiliation(s)
- Megan J Ritter
- Department of Medicine, Section of Endocrinology, Diabetes, Nutrition and Weight Management, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA
- Division of Endocrinology, Diabetes and Metabolism, Joan and Sanford I. Weill Department of Medicine, New York, NY 10021, USA
| | - Izuki Amano
- Department of Medicine, Section of Endocrinology, Diabetes, Nutrition and Weight Management, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA
- Division of Endocrinology, Diabetes and Metabolism, Joan and Sanford I. Weill Department of Medicine, New York, NY 10021, USA
- Department of Integrative Physiology, Gunma University Graduate School of Medicine, Maebashi, 371-8511, Japan
| | - Anne H van der Spek
- Division of Endocrinology, Diabetes and Metabolism, Joan and Sanford I. Weill Department of Medicine, New York, NY 10021, USA
- Department of Endocrinology, Amsterdam Gastroenterology Endocrinology Metabolism, University of Amsterdam UMC, 1105 AZ Amsterdam, the Netherlands
| | - Adam C Gower
- Boston University Clinical and Translational Science Institute, Boston, MA 02118, USA
| | - Hendrik J Undeutsch
- Department of Medicine, Section of Endocrinology, Diabetes, Nutrition and Weight Management, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA
- Division of Endocrinology, Diabetes and Metabolism, Joan and Sanford I. Weill Department of Medicine, New York, NY 10021, USA
| | - Victor A P Rodrigues
- Department of Medicine, Section of Endocrinology, Diabetes, Nutrition and Weight Management, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA
| | - Hanix E Daniel
- Division of Endocrinology, Diabetes and Metabolism, Joan and Sanford I. Weill Department of Medicine, New York, NY 10021, USA
| | - Anthony N Hollenberg
- Department of Medicine, Section of Endocrinology, Diabetes, Nutrition and Weight Management, Boston University Chobanian and Avedisian School of Medicine, Boston, MA 02118, USA
- Division of Endocrinology, Diabetes and Metabolism, Joan and Sanford I. Weill Department of Medicine, New York, NY 10021, USA
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12
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Dong J, Scott TG, Mukherjee R, Guertin MJ. ZNF143 binds DNA and stimulates transcripstion initiation to activate and repress direct target genes. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.05.13.594008. [PMID: 38798607 PMCID: PMC11118474 DOI: 10.1101/2024.05.13.594008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/29/2024]
Abstract
Transcription factors bind to sequence motifs and act as activators or repressors. Transcription factors interface with a constellation of accessory cofactors to regulate distinct mechanistic steps to regulate transcription. We rapidly degraded the essential and ubiquitously expressed transcription factor ZNF143 to determine its function in the transcription cycle. ZNF143 facilitates RNA Polymerase initiation and activates gene expression. ZNF143 binds the promoter of nearly all its activated target genes. ZNF143 also binds near the site of genic transcription initiation to directly repress a subset of genes. Although ZNF143 stimulates initiation at ZNF143-repressed genes (i.e. those that increase expression upon ZNF143 depletion), the molecular context of binding leads to cis repression. ZNF143 competes with other more efficient activators for promoter access, physically occludes transcription initiation sites and promoter-proximal sequence elements, and acts as a molecular roadblock to RNA Polymerases during early elongation. The term context specific is often invoked to describe transcription factors that have both activation and repression functions. We define the context and molecular mechanisms of ZNF143-mediated cis activation and repression.
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Affiliation(s)
- Jinhong Dong
- Center for Cell Analysis and Modeling, University of Connecticut, Farmington, Connecticut, United States of America
| | - Thomas G Scott
- Department of Biochemistry and Molecular Genetics, University of Virginia, Charlottesville, Virginia, United States of America
| | - Rudradeep Mukherjee
- Center for Cell Analysis and Modeling, University of Connecticut, Farmington, Connecticut, United States of America
| | - Michael J Guertin
- Center for Cell Analysis and Modeling, University of Connecticut, Farmington, Connecticut, United States of America
- Department of Genetics and Genome Sciences, University of Connecticut, Farmington, Connecticut, United States of America
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13
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Gao WY, Chen PY, Hsu HJ, Liou JW, Wu CL, Wu MJ, Yen JH. Xanthohumol, a prenylated chalcone, regulates lipid metabolism by modulating the LXRα/RXR-ANGPTL3-LPL axis in hepatic cell lines and high-fat diet-fed zebrafish models. Biomed Pharmacother 2024; 174:116598. [PMID: 38615609 DOI: 10.1016/j.biopha.2024.116598] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/18/2024] [Revised: 04/08/2024] [Accepted: 04/11/2024] [Indexed: 04/16/2024] Open
Abstract
Angiopoietin-like 3 (ANGPTL3) acts as an inhibitor of lipoprotein lipase (LPL), impeding the breakdown of triglyceride-rich lipoproteins (TGRLs) in circulation. Targeting ANGPTL3 is considered a novel strategy for improving dyslipidemia and atherosclerotic cardiovascular diseases (ASCVD). Hops (Humulus lupulus L.) contain several bioactive prenylflavonoids, including xanthohumol (Xan), isoxanthohumol (Isoxan), 6-prenylnaringenin (6-PN), and 8-prenylnaringenin (8-PN), with the potential to manage lipid metabolism. The aim of this study was to investigate the lipid-lowering effects of Xan, the effective prenylated chalcone in attenuating ANGPTL3 transcriptional activity, both in vitro using hepatic cells and in vivo using zebrafish models, along with exploring the underlying mechanisms. Xan (10 and 20 μM) significantly reduced ANGPTL3 mRNA and protein expression in HepG2 and Huh7 cells, leading to a marked decrease in secreted ANGPTL3 proteins via hepatic cells. In animal studies, orally administered Xan significantly alleviated plasma triglyceride (TG) and cholesterol levels in zebrafish fed a high-fat diet. Furthermore, it reduced hepatic ANGPTL3 protein levels and increased LPL activity in zebrafish models, indicating its potential to modulate lipid profiles in circulation. Furthermore, molecular docking results predicted that Xan exhibits a higher binding affinity to interact with liver X receptor α (LXRα) and retinoic acid X receptor (RXR) than their respective agonists, T0901317 and 9-Cis-retinoic acid (9-Cis-RA). We observed that Xan suppressed hepatic ANGPTL3 expression by antagonizing the LXRα/RXR-mediated transcription. These findings suggest that Xan ameliorates dyslipidemia by modulating the LXRα/RXR-ANGPTL3-LPL axis. Xan represents a novel potential inhibitor of ANGPTL3 for the prevention or treatment of ASCVD.
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Affiliation(s)
- Wan-Yun Gao
- Institute of Medical Sciences, Tzu Chi University, Hualien 970374, Taiwan
| | - Pei-Yi Chen
- Laboratory of Medical Genetics, Genetic Counseling Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970374, Taiwan; Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 970374, Taiwan
| | - Hao-Jen Hsu
- Department of Biomedical Science and Engineering, Tzu Chi University, Hualien 970374, Taiwan
| | - Je-Wen Liou
- Department of Biochemistry, School of Medicine, Tzu Chi University, Hualien 970374, Taiwan
| | - Chia-Ling Wu
- Laboratory of Medical Genetics, Genetic Counseling Center, Hualien Tzu Chi Hospital, Buddhist Tzu Chi Medical Foundation, Hualien 970374, Taiwan
| | - Ming-Jiuan Wu
- Department of Biotechnology, Chia Nan University of Pharmacy and Science, Tainan 717301, Taiwan
| | - Jui-Hung Yen
- Institute of Medical Sciences, Tzu Chi University, Hualien 970374, Taiwan; Department of Molecular Biology and Human Genetics, Tzu Chi University, Hualien 970374, Taiwan.
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14
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Hauck AK, Mehmood R, Carpenter BJ, Frankfurter MT, Tackenberg MC, Inoue SI, Krieg MK, Cassim Bawa FN, Midha MK, Zundell DM, Batmanov K, Lazar MA. Nuclear receptor corepressors non-canonically drive glucocorticoid receptor-dependent activation of hepatic gluconeogenesis. Nat Metab 2024; 6:825-836. [PMID: 38622413 PMCID: PMC11459266 DOI: 10.1038/s42255-024-01029-4] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/06/2023] [Accepted: 03/07/2024] [Indexed: 04/17/2024]
Abstract
Nuclear receptor corepressors (NCoRs) function in multiprotein complexes containing histone deacetylase 3 (HDAC3) to alter transcriptional output primarily through repressive chromatin remodelling at target loci1-5. In the liver, loss of HDAC3 causes a marked hepatosteatosis largely because of de-repression of genes involved in lipid metabolism6,7; however, the individual roles and contribution of other complex members to hepatic and systemic metabolic regulation are unclear. Here we show that adult loss of both NCoR1 and NCoR2 (double knockout (KO)) in hepatocytes phenocopied the hepatomegalic fatty liver phenotype of HDAC3 KO. In addition, double KO livers exhibited a dramatic reduction in glycogen storage and gluconeogenic gene expression that was not observed with hepatic KO of individual NCoRs or HDAC3, resulting in profound fasting hypoglycaemia. This surprising HDAC3-independent activation function of NCoR1 and NCoR2 is due to an unexpected loss of chromatin accessibility on deletion of NCoRs that prevented glucocorticoid receptor binding and stimulatory effect on gluconeogenic genes. These studies reveal an unanticipated, non-canonical activation function of NCoRs that is required for metabolic health.
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Affiliation(s)
- Amy K Hauck
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Rashid Mehmood
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Bryce J Carpenter
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Maxwell T Frankfurter
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Michael C Tackenberg
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Shin-Ichi Inoue
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Maria K Krieg
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Fathima N Cassim Bawa
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Mohit K Midha
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Delaine M Zundell
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Kirill Batmanov
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA
| | - Mitchell A Lazar
- Institute for Diabetes, Obesity, and Metabolism, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
- Division of Endocrinology, Diabetes, and Metabolism, Department of Medicine, Perelman School of Medicine, University of Pennsylvania, Philadelphia, PA, USA.
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15
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da Silva MI, Ott T. Effects of conceptus proteins on endometrium and blood leukocytes of dairy cattle using transcriptome and meta-analysis. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2024:2024.04.25.591148. [PMID: 38712302 PMCID: PMC11071483 DOI: 10.1101/2024.04.25.591148] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 05/08/2024]
Abstract
This study investigates the short and long-term effects of IFNT and PAG on the transcriptome of endometrium and blood leukocytes. Holstein heifers received intrauterine infusions of one of the following treatments: 20 mL of a 200 μg/mL bovine serum albumin solution (BSA; vehicle) from day 14 to 16 of the estrous cycle (BSA), vehicle + 10 μg/mL of IFNT from day 14 to 16 (IFNT3), vehicle + 10 μg/mL of IFNT from day 14 to 19 (IFNT6), and vehicle + 10 μg/mL of IFNT from day 14 to 16 followed by vehicle + 10 μg/mL of IFNT + 5 μg/mL of PAG from day 17 to 19 (IFNT+PAG). RNA-seq analysis was performed in endometrial biopsies and blood leukocytes collected after treatments. Acute IFNT signaling in the endometrium (IFNT3 vs BSA), induced differentially expressed genes (DEG) associated with interferon activation, immune response, inflammation, cell death, and inhibited vesicle transport and extracellular matrix remodeling. Prolonged IFNT signaling (IFNT6 vs IFNT3) altered gene expression related to cell invasion, retinoic acid signaling, and embryo implantation. In contrast, PAG induced numerous DEG in blood leukocytes but only 4 DEG in the endometrium. In blood leukocytes, PAG stimulated genes involved in development and TGFB signaling while inhibiting interferon signaling and cell migration. Overall, IFNT is a primary regulator of endometrial gene expression, while PAG predominantly affected the transcriptome of circulating immune cells during early pregnancy. Further research is essential to fully grasp the roles of identified DEG in both the endometrium and blood leukocytes.
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Affiliation(s)
- Maria Isabel da Silva
- Department of Animal Science, Center for Reproductive Biology and Health, Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA
| | - Troy Ott
- Department of Animal Science, Center for Reproductive Biology and Health, Huck Institutes of the Life Sciences, Pennsylvania State University, University Park, PA, USA
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16
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Bennett SN, Chang AB, Rogers FD, Jones P, Peña CJ. Thyroid hormones mediate the impact of early-life stress on ventral tegmental area gene expression and behavior. Horm Behav 2024; 159:105472. [PMID: 38141539 PMCID: PMC10922504 DOI: 10.1016/j.yhbeh.2023.105472] [Citation(s) in RCA: 7] [Impact Index Per Article: 7.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/27/2023] [Revised: 11/17/2023] [Accepted: 12/12/2023] [Indexed: 12/25/2023]
Abstract
Proper thyroid function is essential to the developing brain, including dopamine neuron differentiation, growth, and maintenance. Stress across the lifespan impacts thyroid hormone signaling and anxiety disorders and depression have been associated with thyroid dysfunction (both hypo- and hyper-active). However, less is known about how stress during postnatal development impacts thyroid function and related brain development. Our previous work in mice demonstrated that early-life stress (ELS) transiently impinged on expression of a transcription factor in dopamine neurons, Otx2, shown to be regulated by thyroid hormones. We hypothesized that thyroid hormone signaling may link experience of ELS with transcriptional dysregulation within the dopaminergic midbrain, and ultimately behavior. Here, we find that ELS transiently increases thyroid-stimulating hormone levels (inversely related to thyroid signaling) in both male and female mice at P21, an effect which recovers by adolescence. We next tested whether transient treatment of ELS mice with synthetic thyroid hormone (levothyroxine, LT4) could ameliorate the impact of ELS on sensitivity to future stress, and on expression of genes related to dopamine neuron development and maintenance, thyroid signaling, and plasticity within the ventral tegmental area. Among male mice, but not females, juvenile LT4 treatment prevented hypersensitivity to adult stress. We also found that rescuing developmental deficits in thyroid hormone signaling after ELS restored levels of some genes altered directly by ELS, and prevented alterations in expression of other genes sensitive to the second hit of adult stress. These findings suggest that thyroid signaling mediates the deleterious impact of ELS on VTA development, and that temporary treatment of hypothyroidism after ELS may be sufficient to prevent future stress hypersensitivity.
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Affiliation(s)
| | - Austin B Chang
- Princeton Neuroscience Institute, Princeton University, USA
| | - Forrest D Rogers
- Princeton Neuroscience Institute, Princeton University, USA; Department of Molecular Biology, Princeton University, USA
| | - Parker Jones
- Princeton Neuroscience Institute, Princeton University, USA
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17
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Manickasamy MK, Sajeev A, BharathwajChetty B, Alqahtani MS, Abbas M, Hegde M, Aswani BS, Shakibaei M, Sethi G, Kunnumakkara AB. Exploring the nexus of nuclear receptors in hematological malignancies. Cell Mol Life Sci 2024; 81:78. [PMID: 38334807 PMCID: PMC10858172 DOI: 10.1007/s00018-023-05085-z] [Citation(s) in RCA: 4] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/21/2023] [Revised: 11/16/2023] [Accepted: 12/03/2023] [Indexed: 02/10/2024]
Abstract
Hematological malignancies (HM) represent a subset of neoplasms affecting the blood, bone marrow, and lymphatic systems, categorized primarily into leukemia, lymphoma, and multiple myeloma. Their prognosis varies considerably, with a frequent risk of relapse despite ongoing treatments. While contemporary therapeutic strategies have extended overall patient survival, they do not offer cures for advanced stages and often lead to challenges such as acquisition of drug resistance, recurrence, and severe side effects. The need for innovative therapeutic targets is vital to elevate both survival rates and patients' quality of life. Recent research has pivoted towards nuclear receptors (NRs) due to their role in modulating tumor cell characteristics including uncontrolled proliferation, differentiation, apoptosis evasion, invasion and migration. Existing evidence emphasizes NRs' critical role in HM. The regulation of NR expression through agonists, antagonists, or selective modulators, contingent upon their levels, offers promising clinical implications in HM management. Moreover, several anticancer agents targeting NRs have been approved by the Food and Drug Administration (FDA). This review highlights the integral function of NRs in HM's pathophysiology and the potential benefits of therapeutically targeting these receptors, suggesting a prospective avenue for more efficient therapeutic interventions against HM.
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Affiliation(s)
- Mukesh Kumar Manickasamy
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Anjana Sajeev
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Bandari BharathwajChetty
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, 61421, Abha, Saudi Arabia
- BioImaging Unit, Space Research Centre, University of Leicester, Michael Atiyah Building, Leicester, LE1 7RH, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, 61421, Abha, Saudi Arabia
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Babu Santha Aswani
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India
| | - Mehdi Shakibaei
- Chair of Vegetative Anatomy, Department of Human-Anatomy, Musculoskeletal Research Group and Tumor Biology, Institute of Anatomy, Ludwig-Maximilian-University, 80336, Munich, Germany
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
- NUS Centre for Cancer Research (N2CR), Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117599, Singapore.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati (IITG), Guwahati, Assam, 781039, India.
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18
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Ashton AW, Dhanjal HK, Rossner B, Mahmood H, Patel VI, Nadim M, Lota M, Shahid F, Li Z, Joyce D, Pajkos M, Dosztányi Z, Jiao X, Pestell RG. Acetylation of nuclear receptors in health and disease: an update. FEBS J 2024; 291:217-236. [PMID: 36471658 DOI: 10.1111/febs.16695] [Citation(s) in RCA: 8] [Impact Index Per Article: 8.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/04/2022] [Revised: 10/17/2022] [Accepted: 12/05/2022] [Indexed: 12/12/2022]
Abstract
Lysine acetylation is a common reversible post-translational modification of proteins that plays a key role in regulating gene expression. Nuclear receptors (NRs) include ligand-inducible transcription factors and orphan receptors for which the ligand is undetermined, which together regulate the expression of genes involved in development, metabolism, homeostasis, reproduction and human diseases including cancer. Since the original finding that the ERα, AR and HNF4 are acetylated, we now understand that the vast majority of NRs are acetylated and that this modification has profound effects on NR function. Acetylation sites are often conserved and involve both ordered and disordered regions of NRs. The acetylated residues function as part of an intramolecular signalling platform intersecting phosphorylation, methylation and other modifications. Acetylation of NR has been shown to impact recruitment into chromatin, co-repressor and coactivator complex formation, sensitivity and specificity of regulation by ligand and ligand antagonists, DNA binding, subcellular distribution and transcriptional activity. A growing body of evidence in mice indicates a vital role for NR acetylation in metabolism. Additionally, mutations of the NR acetylation site occur in human disease. This review focuses on the role of NR acetylation in coordinating signalling in normal physiology and disease.
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Affiliation(s)
- Anthony W Ashton
- Xavier University School of Medicine at Aruba, Oranjestad, Aruba
- Lankenau Institute for Medical Research, Wynnewood, PA, USA
| | | | - Benjamin Rossner
- Xavier University School of Medicine at Aruba, Oranjestad, Aruba
| | - Huma Mahmood
- Xavier University School of Medicine at Aruba, Oranjestad, Aruba
| | - Vivek I Patel
- Xavier University School of Medicine at Aruba, Oranjestad, Aruba
| | - Mohammad Nadim
- Xavier University School of Medicine at Aruba, Oranjestad, Aruba
| | - Manpreet Lota
- Xavier University School of Medicine at Aruba, Oranjestad, Aruba
| | - Farhan Shahid
- Xavier University School of Medicine at Aruba, Oranjestad, Aruba
| | - Zhiping Li
- Xavier University School of Medicine at Aruba, Oranjestad, Aruba
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA, USA
| | - David Joyce
- Medical School, Faculty of Health and Medical Sciences, The University of Western Australia, Crawley, WA, Australia
| | - Matyas Pajkos
- Department of Biochemistry, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Zsuzsanna Dosztányi
- Department of Biochemistry, ELTE Eötvös Loránd University, Budapest, Hungary
| | - Xuanmao Jiao
- Xavier University School of Medicine at Aruba, Oranjestad, Aruba
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA, USA
| | - Richard G Pestell
- Xavier University School of Medicine at Aruba, Oranjestad, Aruba
- Pennsylvania Cancer and Regenerative Medicine Research Center, Baruch S. Blumberg Institute, Wynnewood, PA, USA
- The Wistar Cancer Center, Philadelphia, PA, USA
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19
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Zhang R, Dong Y, Liu Y, Moezzi D, Ghorbani S, Mirzaei R, Lozinski BM, Dunn JF, Yong VW, Xue M. Enhanced liver X receptor signalling reduces brain injury and promotes tissue regeneration following experimental intracerebral haemorrhage: roles of microglia/macrophages. Stroke Vasc Neurol 2023; 8:486-502. [PMID: 37137522 PMCID: PMC10800269 DOI: 10.1136/svn-2023-002331] [Citation(s) in RCA: 13] [Impact Index Per Article: 6.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2023] [Accepted: 04/20/2023] [Indexed: 05/05/2023] Open
Abstract
BACKGROUND Inflammation-exacerbated secondary brain injury and limited tissue regeneration are barriers to favourable prognosis after intracerebral haemorrhage (ICH). As a regulator of inflammation and lipid metabolism, Liver X receptor (LXR) has the potential to alter microglia/macrophage (M/M) phenotype, and assist tissue repair by promoting cholesterol efflux and recycling from phagocytes. To support potential clinical translation, the benefits of enhanced LXR signalling are examined in experimental ICH. METHODS Collagenase-induced ICH mice were treated with the LXR agonist GW3965 or vehicle. Behavioural tests were conducted at multiple time points. Lesion and haematoma volume, and other brain parameters were assessed using multimodal MRI with T2-weighted, diffusion tensor imaging and dynamic contrast-enhanced MRI sequences. The fixed brain cryosections were stained and confocal microscopy was applied to detect LXR downstream genes, M/M phenotype, lipid/cholesterol-laden phagocytes, oligodendrocyte lineage cells and neural stem cells. Western blot and real-time qPCR were also used. CX3CR1CreER: Rosa26iDTR mice were employed for M/M-depletion experiments. RESULTS GW3965 treatment reduced lesion volume and white matter injury, and promoted haematoma clearance. Treated mice upregulated LXR downstream genes including ABCA1 and Apolipoprotein E, and had reduced density of M/M that apparently shifted from proinflammatory interleukin-1β+ to Arginase1+CD206+ regulatory phenotype. Fewer cholesterol crystal or myelin debris-laden phagocytes were observed in GW3965 mice. LXR activation increased the number of Olig2+PDGFRα+ precursors and Olig2+CC1+ mature oligodendrocytes in perihaematomal regions, and elevated SOX2+ or nestin+ neural stem cells in lesion and subventricular zone. MRI results supported better lesion recovery by GW3965, and this was corroborated by return to pre-ICH values of functional rotarod activity. The therapeutic effects of GW3965 were abrogated by M/M depletion in CX3CR1CreER: Rosa26iDTR mice. CONCLUSIONS LXR agonism using GW3965 reduced brain injury, promoted beneficial properties of M/M and facilitated tissue repair correspondent with enhanced cholesterol recycling.
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Affiliation(s)
- Ruiyi Zhang
- Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
- Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
| | - Yifei Dong
- Department of Biochemistry, Microbiology, & Immunology, College of Medicine, University of Saskatchewan, Saskatoon, Saskatchewan, Canada
| | - Yang Liu
- Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
| | - Dorsa Moezzi
- Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
| | - Samira Ghorbani
- Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
| | - Reza Mirzaei
- Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
| | - Brian M Lozinski
- Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
| | - Jeff F Dunn
- Department of Radiology, University of Calgary, Calgary, Alberta, Canada
| | - V Wee Yong
- Hotchkiss Brain Institute and Department of Clinical Neurosciences, University of Calgary, Calgary, Alberta, Canada
| | - Mengzhou Xue
- Department of Cerebrovascular Diseases, The Second Affiliated Hospital of Zhengzhou University, Zhengzhou, Henan, China
- Academy of Medical Science, Zhengzhou University, Zhengzhou, Henan, China
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20
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Mukherjee S, Dasgupta S, Panja SS, Adhikari U. Structural insight to human Retinoid X receptor alpha-Thyroid hormone receptor beta heterodimer by molecular modelling and MD-simulation studies: role of conserved water molecules. J Biomol Struct Dyn 2023; 41:9828-9839. [PMID: 36411737 DOI: 10.1080/07391102.2022.2147097] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/01/2022] [Accepted: 11/08/2022] [Indexed: 11/23/2022]
Abstract
The Retinoid X receptor alpha-Thyroid hormone receptor beta (RXRα-THRβ) heterodimer plays an important role in physiological function of humans specially in the growth and development. Extensive MD-simulation studies on the aquated complexes of modelled RXRα-THRβ heterodimer with DNA-duplex have indicated the role of some conserved/semiconserved water molecules in the complexation process in presence or absence of Triiodothyronine (T3) and 9-cis retinoic acid (9CR) in the respective Ligand Binding Domain (LBD) domain. Among the seventeen conserved/semi-conserved water molecules, the W1-W4 water centers have been observed to mediate the interaction between the residues of A-chain (DBD of RXR) to consensus sequence (C-chain) of DNA. The W5-W8 water centers involve in recognition of the residues of B-chain (DBD of THR) to C-chain of DNA. The W9-W13 centers have connected the different residues of B-chain (THR) to D-chain of DNA through H-bonds, whereas W14-W17 water molecules were involved in the interaction of A-chain's (RXR) residues to D-chain of DNA. In our previous study with homodimeric THRβ from Rattus norvegicus we have identified fifteen conserved water molecules at the DNA-DBD interface. Moreover, the conformational flexibility of Met313 (in the LBD of THR) from open to close form in presence or absence of T3 molecule in the holo and Apo-protein may provide a plausible rational on the possible role of that residue to acts as gate which could restrict the solvent molecules to enter into the hydrophobic T3-binding pocket of LBD during the absence of ligand molecule and thus could help the stabilization of that domain in THRβ structure.Communicated by Ramaswamy H. Sarma.
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Affiliation(s)
- Soumita Mukherjee
- Department of Chemistry, National Institute of Technology-Durgapur, West Bengal, India
| | - Subrata Dasgupta
- Department of Bioscience and Bioengineering, Indian Institute of Technology-Bombay, Mumbai, India
| | - Sujit Sankar Panja
- Department of Chemistry, National Institute of Technology-Durgapur, West Bengal, India
| | - Utpal Adhikari
- Department of Chemistry, National Institute of Technology-Durgapur, West Bengal, India
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21
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David NA, Lee RD, LaRue RS, Joo S, Farrar MA. Nuclear corepressors NCOR1 and NCOR2 entrain thymocyte signaling, selection, and emigration. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.09.27.559810. [PMID: 37808728 PMCID: PMC10557688 DOI: 10.1101/2023.09.27.559810] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 10/10/2023]
Abstract
T cell development proceeds via discrete stages that require both gene induction and gene repression. Transcription factors direct gene repression by associating with corepressor complexes containing chromatin-remodeling enzymes; the corepressors NCOR1 and NCOR2 recruit histone deacetylases to these complexes to silence transcription of target genes. Earlier work identified the importance of NCOR1 in promoting the survival of positively-selected thymocytes. Here, we used flow cytometry and single-cell RNA sequencing to identify a broader role for NCOR1 and NCOR2 in regulating thymocyte development. Using Cd4-cre mice, we found that conditional deletion of NCOR2 had no effect on thymocyte development, whereas conditional deletion of NCOR1 had a modest effect. In contrast, Cd4-cre x Ncor1f/f x Ncor2f/f mice exhibited a significant block in thymocyte development at the DP to SP transition. Combined NCOR1/2 deletion resulted in increased signaling through the T cell receptor, ultimately resulting in elevated BIM expression and increased negative selection. The NF-κB, NUR77, and MAPK signaling pathways were also upregulated in the absence of NCOR1/2, contributing to altered CD4/CD8 lineage commitment, TCR rearrangement, and thymocyte emigration. Taken together, our data identify multiple critical roles for the combined action of NCOR1 and NCOR2 over the course of thymocyte development.
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Affiliation(s)
- Natalie A David
- Center for Immunology, Masonic Cancer Center, Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, MN 55455
| | - Robin D Lee
- Center for Immunology, Masonic Cancer Center, Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, MN 55455
| | - Rebecca S LaRue
- Minnesota Supercomputing Institute, University of Minnesota, Minneapolis, MN 55455
| | - Sookyong Joo
- Center for Immunology, Masonic Cancer Center, Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, MN 55455
| | - Michael A Farrar
- Center for Immunology, Masonic Cancer Center, Department of Laboratory Medicine and Pathology, Medical School, University of Minnesota, Minneapolis, MN 55455
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22
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Miziak P, Baran M, Błaszczak E, Przybyszewska-Podstawka A, Kałafut J, Smok-Kalwat J, Dmoszyńska-Graniczka M, Kiełbus M, Stepulak A. Estrogen Receptor Signaling in Breast Cancer. Cancers (Basel) 2023; 15:4689. [PMID: 37835383 PMCID: PMC10572081 DOI: 10.3390/cancers15194689] [Citation(s) in RCA: 44] [Impact Index Per Article: 22.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/19/2023] [Revised: 09/19/2023] [Accepted: 09/20/2023] [Indexed: 10/15/2023] Open
Abstract
Estrogen receptor (ER) signaling is a critical regulator of cell proliferation, differentiation, and survival in breast cancer (BC) and other hormone-sensitive cancers. In this review, we explore the mechanism of ER-dependent downstream signaling in BC and the role of estrogens as growth factors necessary for cancer invasion and dissemination. The significance of the clinical implications of ER signaling in BC, including the potential of endocrine therapies that target estrogens' synthesis and ER-dependent signal transmission, such as aromatase inhibitors or selective estrogen receptor modulators, is discussed. As a consequence, the challenges associated with the resistance to these therapies resulting from acquired ER mutations and potential strategies to overcome them are the critical point for the new treatment strategies' development.
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Affiliation(s)
- Paulina Miziak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Marzena Baran
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Ewa Błaszczak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Alicja Przybyszewska-Podstawka
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Joanna Kałafut
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Jolanta Smok-Kalwat
- Department of Clinical Oncology, Holy Cross Cancer Centre, 3 Artwinskiego Street, 25-734 Kielce, Poland;
| | - Magdalena Dmoszyńska-Graniczka
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Michał Kiełbus
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
| | - Andrzej Stepulak
- Department of Biochemistry and Molecular Biology, Medical University of Lublin, 1 Chodzki Street, 20-093 Lublin, Poland; (M.B.); (E.B.); (A.P.-P.); (J.K.); (M.D.-G.)
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23
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Hegde M, Girisa S, Naliyadhara N, Kumar A, Alqahtani MS, Abbas M, Mohan CD, Warrier S, Hui KM, Rangappa KS, Sethi G, Kunnumakkara AB. Natural compounds targeting nuclear receptors for effective cancer therapy. Cancer Metastasis Rev 2023; 42:765-822. [PMID: 36482154 DOI: 10.1007/s10555-022-10068-w] [Citation(s) in RCA: 18] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 11/03/2022] [Indexed: 12/13/2022]
Abstract
Human nuclear receptors (NRs) are a family of forty-eight transcription factors that modulate gene expression both spatially and temporally. Numerous biochemical, physiological, and pathological processes including cell survival, proliferation, differentiation, metabolism, immune modulation, development, reproduction, and aging are extensively orchestrated by different NRs. The involvement of dysregulated NRs and NR-mediated signaling pathways in driving cancer cell hallmarks has been thoroughly investigated. Targeting NRs has been one of the major focuses of drug development strategies for cancer interventions. Interestingly, rapid progress in molecular biology and drug screening reveals that the naturally occurring compounds are promising modern oncology drugs which are free of potentially inevitable repercussions that are associated with synthetic compounds. Therefore, the purpose of this review is to draw our attention to the potential therapeutic effects of various classes of natural compounds that target NRs such as phytochemicals, dietary components, venom constituents, royal jelly-derived compounds, and microbial derivatives in the establishment of novel and safe medications for cancer treatment. This review also emphasizes molecular mechanisms and signaling pathways that are leveraged to promote the anti-cancer effects of these natural compounds. We have also critically reviewed and assessed the advantages and limitations of current preclinical and clinical studies on this subject for cancer prophylaxis. This might subsequently pave the way for new paradigms in the discovery of drugs that target specific cancer types.
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Affiliation(s)
- Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Nikunj Naliyadhara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Aviral Kumar
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India
| | - Mohammed S Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha, 61421, Saudi Arabia
- BioImaging Unit, Space Research Centre, University of Leicester, Michael Atiyah Building, Leicester, LE1 7RH, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha, 61421, Saudi Arabia
- Electronics and Communications Department, College of Engineering, Delta University for Science and Technology, 35712, Gamasa, Egypt
| | | | - Sudha Warrier
- Division of Cancer Stem Cells and Cardiovascular Regeneration, School of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, 560065, India
- Cuor Stem Cellutions Pvt Ltd, Manipal Institute of Regenerative Medicine, Manipal Academy of Higher Education (MAHE), Bangalore, 560065, India
| | - Kam Man Hui
- Division of Cellular and Molecular Research, Humphrey Oei Institute of Cancer Research, National Cancer Centre, Singapore, 169610, Singapore
| | | | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore, 117600, Singapore.
| | - Ajaikumar B Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology Guwahati, Guwahati, 781039, Assam, India.
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24
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Bennett SN, Chang AB, Rogers FD, Jones P, Peña CJ. Thyroid hormones mediate the impact of early-life stress on ventral tegmental area gene expression and behavior. BIORXIV : THE PREPRINT SERVER FOR BIOLOGY 2023:2023.08.25.554785. [PMID: 37662236 PMCID: PMC10473690 DOI: 10.1101/2023.08.25.554785] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 09/05/2023]
Abstract
Proper thyroid function is essential to the developing brain, including dopamine neuron differentiation, growth, and maintenance. Stress across the lifespan impacts thyroid hormone signaling and anxiety disorders and depression have been associated with thyroid dysfunction (both hypo- and hyper-active). However, less is known about how stress during postnatal development impacts thyroid function and related brain development. Our previous work in mice demonstrated that early-life stress (ELS) transiently impinged on expression of a transcription factor in dopamine neurons shown to be regulated by thyroid hormones. We hypothesized that thyroid hormone signaling may link experience of ELS with transcriptional dysregulation within the dopaminergic midbrain, and ultimately behavior. Here, we find that ELS transiently increases thyroid-stimulating hormone levels (inversely related to thyroid signaling) in both male and female mice at P21, an effect which recovers by adolescence. We next tested whether transient treatment of ELS mice with synthetic thyroid hormone (levothyroxine, LT4) could ameliorate the impact of ELS on sensitivity to future stress, and on expression of genes related to dopamine neuron development and maintenance, thyroid signaling, and plasticity within the ventral tegmental area. Among male mice, but not females, juvenile LT4 treatment prevented hypersensitivity to adult stress. We also found that rescuing developmental deficits in thyroid hormone signaling after ELS restored levels of some genes altered directly by ELS, and prevented alterations in expression of other genes sensitive to the second hit of adult stress. These findings suggest that thyroid signaling mediates the deleterious impact of ELS on VTA development, and that temporary treatment of hypothyroidism after ELS may be sufficient to prevent future stress hypersensitivity.
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25
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Pratiwi HM, Hirasawa M, Kato K, Munakata K, Ueda S, Moriyama Y, Yu R, Kawanishi T, Tanaka M. Heterochronic development of pelvic fins in zebrafish: possible involvement of temporal regulation of pitx1 expression. Front Cell Dev Biol 2023; 11:1170691. [PMID: 37691823 PMCID: PMC10483283 DOI: 10.3389/fcell.2023.1170691] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/21/2023] [Accepted: 08/04/2023] [Indexed: 09/12/2023] Open
Abstract
Anterior and posterior paired appendages of vertebrates are notable examples of heterochrony in the relative timing of their development. In teleosts, posterior paired appendages (pelvic fin buds) emerge much later than their anterior paired appendages (pectoral fin buds). Pelvic fin buds of zebrafish (Danio rerio) appear at 3 weeks post-fertilization (wpf) during the larva-to-juvenile transition (metamorphosis), whereas pectoral fin buds arise from the lateral plate mesoderm on the yolk surface at the embryonic stage. Here we explored the mechanism by which presumptive pelvic fin cells maintain their fate, which is determined at the embryonic stage, until the onset of metamorphosis. Expression analysis revealed that transcripts of pitx1, one of the key factors for the development of posterior paired appendages, became briefly detectable in the posterior lateral plate mesoderm at early embryonic stages. Further analysis indicated that the pelvic fin-specific pitx1 enhancer was in the poised state at the larval stage and is activated at the juvenile stage. We discuss the implications of these findings for the heterochronic development of pelvic fin buds.
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Affiliation(s)
| | | | | | | | | | | | | | | | - Mikiko Tanaka
- Department of Life Science and Technology, Tokyo Institute of Technology, Yokohama, Kanagawa, Japan
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26
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Deploey N, Van Moortel L, Rogatsky I, Peelman F, De Bosscher K. The Biologist's Guide to the Glucocorticoid Receptor's Structure. Cells 2023; 12:1636. [PMID: 37371105 PMCID: PMC10297449 DOI: 10.3390/cells12121636] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/09/2023] [Revised: 06/07/2023] [Accepted: 06/09/2023] [Indexed: 06/29/2023] Open
Abstract
The glucocorticoid receptor α (GRα) is a member of the nuclear receptor superfamily and functions as a glucocorticoid (GC)-responsive transcription factor. GR can halt inflammation and kill off cancer cells, thus explaining the widespread use of glucocorticoids in the clinic. However, side effects and therapy resistance limit GR's therapeutic potential, emphasizing the importance of resolving all of GR's context-specific action mechanisms. Fortunately, the understanding of GR structure, conformation, and stoichiometry in the different GR-controlled biological pathways is now gradually increasing. This information will be crucial to close knowledge gaps on GR function. In this review, we focus on the various domains and mechanisms of action of GR, all from a structural perspective.
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Affiliation(s)
- Nick Deploey
- VIB Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium; (N.D.); (L.V.M.); (F.P.)
- Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
- Translational Nuclear Receptor Research (TNRR) Laboratory, VIB, 9052 Ghent, Belgium
| | - Laura Van Moortel
- VIB Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium; (N.D.); (L.V.M.); (F.P.)
- Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
- Translational Nuclear Receptor Research (TNRR) Laboratory, VIB, 9052 Ghent, Belgium
| | - Inez Rogatsky
- Hospital for Special Surgery Research Institute, The David Z. Rosensweig Genomics Center, New York, NY 10021, USA;
- Graduate Program in Immunology and Microbial Pathogenesis, Weill Cornell Graduate School of Medical Sciences, New York, NY 10065, USA
| | - Frank Peelman
- VIB Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium; (N.D.); (L.V.M.); (F.P.)
- Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
| | - Karolien De Bosscher
- VIB Center for Medical Biotechnology, VIB, 9052 Ghent, Belgium; (N.D.); (L.V.M.); (F.P.)
- Department of Biomolecular Medicine, Ghent University, 9000 Ghent, Belgium
- Translational Nuclear Receptor Research (TNRR) Laboratory, VIB, 9052 Ghent, Belgium
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27
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Harper M, Hu Y, Donahue J, Acosta B, Dievenich Braes F, Nguyen S, Zeng J, Barbaro J, Lee H, Bui H, McMenamin SK. Thyroid hormone regulates proximodistal patterning in fin rays. Proc Natl Acad Sci U S A 2023; 120:e2219770120. [PMID: 37186843 PMCID: PMC10214145 DOI: 10.1073/pnas.2219770120] [Citation(s) in RCA: 12] [Impact Index Per Article: 6.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/05/2022] [Accepted: 03/26/2023] [Indexed: 05/17/2023] Open
Abstract
Processes that regulate size and patterning along an axis must be highly integrated to generate robust shapes; relative changes in these processes underlie both congenital disease and evolutionary change. Fin length mutants in zebrafish have provided considerable insight into the pathways regulating fin size, yet signals underlying patterning have remained less clear. The bony rays of the fins possess distinct patterning along the proximodistal axis, reflected in the location of ray bifurcations and the lengths of ray segments, which show progressive shortening along the axis. Here, we show that thyroid hormone (TH) regulates aspects of proximodistal patterning of the caudal fin rays, regardless of fin size. TH promotes distal gene expression patterns, coordinating ray bifurcations and segment shortening with skeletal outgrowth along the proximodistal axis. This distalizing role for TH is conserved between development and regeneration, in all fins (paired and medial), and between Danio species as well as distantly related medaka. During regenerative outgrowth, TH acutely induces Shh-mediated skeletal bifurcation. Zebrafish have multiple nuclear TH receptors, and we found that unliganded Thrab-but not Thraa or Thrb-inhibits the formation of distal features. Broadly, these results demonstrate that proximodistal morphology is regulated independently from size-instructive signals. Modulating proximodistal patterning relative to size-either through changes to TH metabolism or other hormone-independent pathways-can shift skeletal patterning in ways that recapitulate aspects of fin ray diversity found in nature.
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Affiliation(s)
- Melody Harper
- Biology Department, Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, MA02467
| | - Yinan Hu
- Biology Department, Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, MA02467
| | - Joan Donahue
- Biology Department, Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, MA02467
| | - Benjamin Acosta
- Biology Department, Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, MA02467
| | - Flora Dievenich Braes
- Biology Department, Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, MA02467
| | - Stacy Nguyen
- Biology Department, Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, MA02467
| | - Jenny Zeng
- Biology Department, Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, MA02467
| | - Julianna Barbaro
- Biology Department, Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, MA02467
| | - Hyungwoo Lee
- Biology Department, Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, MA02467
| | - Hoa Bui
- Biology Department, Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, MA02467
| | - Sarah K. McMenamin
- Biology Department, Morrissey College of Arts and Sciences, Boston College, Chestnut Hill, MA02467
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28
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Jamshed F, Dashti F, Ouyang X, Mehal WZ, Banini BA. New uses for an old remedy: Digoxin as a potential treatment for steatohepatitis and other disorders. World J Gastroenterol 2023; 29:1824-1837. [PMID: 37032732 PMCID: PMC10080697 DOI: 10.3748/wjg.v29.i12.1824] [Citation(s) in RCA: 4] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 11/19/2022] [Revised: 01/12/2023] [Accepted: 03/14/2023] [Indexed: 03/28/2023] Open
Abstract
Repurposing of the widely available and relatively cheap generic cardiac gly-coside digoxin for non-cardiac indications could have a wide-ranging impact on the global burden of several diseases. Over the past several years, there have been significant advances in the study of digoxin pharmacology and its potential non-cardiac clinical applications, including anti-inflammatory, antineoplastic, metabolic, and antimicrobial use. Digoxin holds promise in the treatment of gastrointestinal disease, including nonalcoholic steatohepatitis and alcohol-associated steatohepatitis as well as in obesity, cancer, and treatment of viral infections, among other conditions. In this review, we provide a summary of the clinical uses of digoxin to date and discuss recent research on its emerging applications.
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Affiliation(s)
- Fatima Jamshed
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT 06510, United States
- Griffin Hospital-Yale University, Derby, CT 06418, United States
| | - Farzaneh Dashti
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT 06510, United States
| | - Xinshou Ouyang
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT 06510, United States
| | - Wajahat Z Mehal
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT 06510, United States
- West Haven Veterans Medical Center, West Haven, CT 06516, United States
| | - Bubu A Banini
- Section of Digestive Diseases, Yale School of Medicine, New Haven, CT 06510, United States
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29
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Tanizaki Y, Bao L, Shi YB. Steroid-receptor coactivator complexes in thyroid hormone-regulation of Xenopus metamorphosis. VITAMINS AND HORMONES 2023; 123:483-502. [PMID: 37717995 PMCID: PMC11274430 DOI: 10.1016/bs.vh.2023.02.003] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 03/11/2023]
Abstract
Anuran metamorphosis is perhaps the most drastic developmental change regulated by thyroid hormone (T3) in vertebrate. It mimics the postembryonic development in mammals when many organs/tissues mature into adult forms and plasma T3 level peaks. T3 functions by regulating target gene transcription through T3 receptors (TRs), which can recruit corepressor or coactivator complexes to target genes in the absence or presence of T3, respectively. By using molecular and genetic approaches, we and others have investigated the role of corepressor or coactivator complexes in TR function during the development of two highly related anuran species, the pseudo-tetraploid Xenopus laevis and diploid Xenopus tropicalis. Here we will review some of these studies that demonstrate a critical role of coactivator complexes, particularly those containing steroid receptor coactivator (SRC) 3, in regulating metamorphic rate and ensuring the completion of metamorphosis.
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Affiliation(s)
- Yuta Tanizaki
- Section on Molecular Morphogenesis, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Lingyu Bao
- Section on Molecular Morphogenesis, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States
| | - Yun-Bo Shi
- Section on Molecular Morphogenesis, Eunice Kennedy Shriver National Institute of Child Health and Human Development (NICHD), National Institutes of Health (NIH), Bethesda, MD, United States.
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30
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Gustafsson JÅ, Li XC, Suh JH, Lou X. A structural perspective of liver X receptors. VITAMINS AND HORMONES 2023; 123:231-247. [PMID: 37717986 DOI: 10.1016/bs.vh.2023.01.008] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/09/2023]
Abstract
Liver X receptors α and β are members of the nuclear receptor family, which comprise a flexible N-terminal domain, a DNA binding domain, a hinge linker, and a ligand binding domain. Liver X receptors are important regulators of cholesterol and lipid homeostasis by controlling the transcription of numerous genes. Key to their transcriptional role is synergetic interaction among the domains. DNA binding domain binds on DNA; ligand binding domain is a crucial switch to control the transcription activity through conformational change caused by ligand binding. The Liver X receptors form heterodimers with retinoid X receptor and then the liganded heterodimer may recruit other necessary transcription components to form an active transcription complex.
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Affiliation(s)
- Jan-Åke Gustafsson
- Department of Cell Biology and Biochemistry, Center for Nuclear Receptors and Cell Signaling, University of Houston, Houston, TX, United States; Department of Biosciences and Nutrition, Karolinska Institutet, Huddinge, Sweden.
| | - Xian Chang Li
- Immunobiology and Transplant Science Center and Department of Surgery, Houston Methodist Research Institute, Houston, TX, United States; Department of Surgery, Weill Cornell Medical College of Cornell University, New York, NY, United States
| | - Ji Ho Suh
- Department of Anesthesiology, McGovern Medical School, The University of Texas Health Science Center at Houston, Houston, TX, United States
| | - Xiaohua Lou
- Immunobiology and Transplant Science Center and Department of Surgery, Houston Methodist Research Institute, Houston, TX, United States.
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Wang L, Zhang Q, Ye L, Ye X, Yang W, Zhang H, Zhou X, Ren Y, Ma L, Zhang X, Mei C, Xu G, Li K, Luo Y, Jiang L, Lin P, Zhu S, Lang W, Wang Y, Shen C, Han Y, Liu X, Yang H, Lu C, Sun J, Jin J, Tong H. All-trans retinoic acid enhances the cytotoxic effect of decitabine on myelodysplastic syndromes and acute myeloid leukaemia by activating the RARα-Nrf2 complex. Br J Cancer 2023; 128:691-701. [PMID: 36482192 PMCID: PMC9938271 DOI: 10.1038/s41416-022-02074-0] [Citation(s) in RCA: 11] [Impact Index Per Article: 5.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/26/2022] [Revised: 11/12/2022] [Accepted: 11/15/2022] [Indexed: 12/13/2022] Open
Abstract
BACKGROUND Decitabine (DAC) is used as the first-line therapy in patients with higher-risk myelodysplastic syndromes (HR-MDS) and elderly acute myeloid leukaemia (AML) patients unsuitable for intensive chemotherapy. However, the clinical outcomes of patients treated with DAC as a monotherapy are far from satisfactory. Adding all-trans retinoic acid (ATRA) to DAC reportedly benefitted MDS and elderly AML patients. However, the underlying mechanisms remain unclear and need further explorations from laboratory experiments. METHODS We used MDS and AML cell lines and primary cells to evaluate the combined effects of DAC and ATRA as well as the underlying mechanisms. We used the MOLM-13-luciferase murine xenograft model to verify the enhanced cytotoxic effect of the drug combination. RESULTS The combination treatment reduced the viability of MDS/AML cells in vitro, delayed leukaemia progress, and extended survival in murine xenograft models compared to non- and mono-drug treated models. DAC application as a single agent induced Nrf2 activation and downstream antioxidative response, and restrained reactive oxygen species (ROS) generation, thus leading to DAC resistance. The addition of ATRA blocked Nrf2 activation by activating the RARα-Nrf2 complex, leading to ROS accumulation and ROS-dependent cytotoxicity. CONCLUSIONS These results demonstrate that combining DAC and ATRA has potential for the clinical treatment of HR-MDS/AML and merits further exploration.
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Affiliation(s)
- Lu Wang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Qi Zhang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Li Ye
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Xingnong Ye
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Wenli Yang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Hua Zhang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Xinping Zhou
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Yanling Ren
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Liya Ma
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Xiang Zhang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Chen Mei
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Gaixiang Xu
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Kongfei Li
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Yingwan Luo
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Lingxu Jiang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Peipei Lin
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Department of Radiotherapy, Taizhou Central Hospital (Taizhou University Hospital), 318000, Taizhou, Zhejiang, China
| | - Shuanghong Zhu
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Wei Lang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Yuxia Wang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Chuying Shen
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Yueyuan Han
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Xiaozhen Liu
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Haiyang Yang
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Chenxi Lu
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
| | - Jie Sun
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, 310058, Hangzhou, Zhejiang, China
| | - Jie Jin
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China
- Cancer Center, Zhejiang University, 310058, Hangzhou, Zhejiang, China
| | - Hongyan Tong
- Department of Hematology, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China.
- Myelodysplastic Syndromes Diagnosis and Therapy Center, The First Affiliated Hospital, Zhejiang University School of Medicine, 310003, Hangzhou, Zhejiang, China.
- Key Laboratory of Hematologic Malignancies, Diagnosis and Treatment, 310003, Hangzhou, Zhejiang, China.
- Cancer Center, Zhejiang University, 310058, Hangzhou, Zhejiang, China.
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Wang M, Roggero VR, Allison LA. Mediator subunit MED1 differentially modulates mutant thyroid hormone receptor intracellular dynamics in Resistance to Thyroid Hormone syndrome. Mol Cell Endocrinol 2023; 559:111781. [PMID: 36191835 PMCID: PMC9985138 DOI: 10.1016/j.mce.2022.111781] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 07/19/2022] [Revised: 09/16/2022] [Accepted: 09/27/2022] [Indexed: 02/03/2023]
Abstract
Thyroid hormone receptor (TR) controls the expression of thyroid hormone (T3)-responsive genes, while undergoing rapid nucleocytoplasmic shuttling. In Resistance to Thyroid Hormone syndrome (RTH), mutant TR fails to activate T3-dependent transcription. Previously, we showed that Mediator subunit 1 (MED1) plays a role in TR nuclear retention. Here, we investigated MED1's effect on RTH mutants using nucleocytoplasmic scoring and fluorescence recovery after photobleaching in transfected cells. MED1 overexpression and knockout did not change the nucleocytoplasmic distribution or intranuclear mobility of C392X and P398R TRα1 at physiological T3 levels. At elevated T3 levels, however, overexpression increased P398R's nuclear retention and MED1 knockout decreased P398R's and A263V's intranuclear mobility, while not impacting C392X. Although A263V TRα1-transfected cells had a high percentage of aggregates, MED1 rescued A263V's impaired intranuclear mobility, suggesting that MED1 ameliorates nonfunctional aggregates. Results correlate with clinical severity, suggesting that altered interaction between MED1 and TRα1 mutants contributes to RTH pathology.
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Affiliation(s)
- Moyao Wang
- Department of Biology, William & Mary, 540 Landrum Drive, Integrated Science Center 3030, Williamsburg, VA, 23185, USA
| | - Vincent R Roggero
- Department of Biology, William & Mary, 540 Landrum Drive, Integrated Science Center 3030, Williamsburg, VA, 23185, USA
| | - Lizabeth A Allison
- Department of Biology, William & Mary, 540 Landrum Drive, Integrated Science Center 3030, Williamsburg, VA, 23185, USA.
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Balagurov KI, Georgiev PG, Bonchuk AN. The NCoR Co-repressor Interacts with the Kaiso Transcription Factor through a Mechanism Different from That of BCL6 Interaction. DOKL BIOCHEM BIOPHYS 2022; 507:326-329. [PMID: 36786995 DOI: 10.1134/s1607672922340026] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/20/2022] [Revised: 10/24/2022] [Accepted: 10/24/2022] [Indexed: 02/15/2023]
Abstract
The vertebrate transcription factor Kaiso binds specifically to methylated DNA sequences using C2H2-type zinc fingers. In addition to C2H2-domains, the BTB/POZ domain, which forms homodimers, is located at the N-terminus of Kaiso. Kaiso, like several other well-studied BTB/POZ proteins, including BCL6, interacts with the NCoR (nuclear co-repressor) protein, which determines the landing of transcriptional repressive complexes on chromatin. Using the yeast two-hybrid system, we have shown that the N-terminal domain of NCoR interacts with the C-terminal zinc fingers of Kaiso, and not with its BTB/POZ domain, as previously assumed. The results obtained demonstrate that NCoR interacts with various transcription factor domains, which can increase the efficiency of attracting NCoR-dependent repressor complexes to regulatory regions of the genome.
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Affiliation(s)
- K I Balagurov
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia.
| | - P G Georgiev
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
| | - A N Bonchuk
- Institute of Gene Biology, Russian Academy of Sciences, Moscow, Russia
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34
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Zhang H, Gao H, Gu Y, John A, Wei L, Huang M, Yu J, Adeosun AA, Weinshilboum RM, Wang L. 3D CRISPR screen in prostate cancer cells reveals PARP inhibitor sensitization through TBL1XR1-SMC3 interaction. Front Oncol 2022; 12:999302. [PMID: 36523978 PMCID: PMC9746894 DOI: 10.3389/fonc.2022.999302] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/20/2022] [Accepted: 11/14/2022] [Indexed: 08/24/2023] Open
Abstract
Poly(ADP-ribose) (PAR) polymerase inhibitors (PARPi) either have been approved or being tested in the clinic for the treatment of a variety of cancers with homologous recombination deficiency (HRD). However, cancer cells can develop resistance to PARPi drugs through various mechanisms, and new biomarkers and combination therapeutic strategies need to be developed to support personalized treatment. In this study, a genome-wide CRISPR screen was performed in a prostate cancer cell line with 3D culture condition which identified novel signals involved in DNA repair pathways. One of these genes, TBL1XR1, regulates sensitivity to PARPi in prostate cancer cells. Mechanistically, we show that TBL1XR1 interacts with and stabilizes SMC3 on chromatin and promotes γH2AX spreading along the chromatin of the cells under DNA replication stress. TBL1XR1-SMC3 double knockdown (knockout) cells have comparable sensitivity to PARPi compared to SMC3 knockdown or TBL1XR1 knockout cells, and more sensitivity than WT cells. Our findings provide new insights into mechanisms underlying response to PARPi or platin compounds in the treatment of malignancies.
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Affiliation(s)
- Huan Zhang
- School of Medicine, Nantong University, Nantong, China
| | - Huanyao Gao
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Yayun Gu
- School of Medicine, Nantong University, Nantong, China
| | - August John
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Lixuan Wei
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Minhong Huang
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Jia Yu
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Adeyemi A. Adeosun
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Richard M. Weinshilboum
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
| | - Liewei Wang
- Division of Clinical Pharmacology, Department of Molecular Pharmacology and Experimental Therapeutics, Mayo Clinic, Rochester, MN, United States
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Aylon Y, Furth N, Mallel G, Friedlander G, Nataraj NB, Dong M, Hassin O, Zoabi R, Cohen B, Drendel V, Salame TM, Mukherjee S, Harpaz N, Johnson R, Aulitzky WE, Yarden Y, Shema E, Oren M. Breast cancer plasticity is restricted by a LATS1-NCOR1 repressive axis. Nat Commun 2022; 13:7199. [PMID: 36443319 PMCID: PMC9705295 DOI: 10.1038/s41467-022-34863-9] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/12/2022] [Accepted: 11/10/2022] [Indexed: 11/29/2022] Open
Abstract
Breast cancer, the most frequent cancer in women, is generally classified into several distinct histological and molecular subtypes. However, single-cell technologies have revealed remarkable cellular and functional heterogeneity across subtypes and even within individual breast tumors. Much of this heterogeneity is attributable to dynamic alterations in the epigenetic landscape of the cancer cells, which promote phenotypic plasticity. Such plasticity, including transition from luminal to basal-like cell identity, can promote disease aggressiveness. We now report that the tumor suppressor LATS1, whose expression is often downregulated in human breast cancer, helps maintain luminal breast cancer cell identity by reducing the chromatin accessibility of genes that are characteristic of a "basal-like" state, preventing their spurious activation. This is achieved via interaction of LATS1 with the NCOR1 nuclear corepressor and recruitment of HDAC1, driving histone H3K27 deacetylation near NCOR1-repressed "basal-like" genes. Consequently, decreased expression of LATS1 elevates the expression of such genes and facilitates slippage towards a more basal-like phenotypic identity. We propose that by enforcing rigorous silencing of repressed genes, the LATS1-NCOR1 axis maintains luminal cell identity and restricts breast cancer progression.
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Affiliation(s)
- Yael Aylon
- grid.13992.300000 0004 0604 7563Department of Molecular Cell Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Noa Furth
- grid.13992.300000 0004 0604 7563Department of Immunology and Regenerative Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Giuseppe Mallel
- grid.13992.300000 0004 0604 7563Department of Molecular Cell Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Gilgi Friedlander
- grid.13992.300000 0004 0604 7563Department of Life Sciences Core Facilities, The Nancy & Stephen Grand Israel National Center for Personalized Medicine (G-INCPM), The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Nishanth Belugali Nataraj
- grid.13992.300000 0004 0604 7563Department of Immunology and Regenerative Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Meng Dong
- grid.502798.10000 0004 0561 903XDr. Margarete Fischer-Bosch-Institute of Clinical Pharmacology and University of Tuebingen, Stuttgart, Germany
| | - Ori Hassin
- grid.13992.300000 0004 0604 7563Department of Molecular Cell Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Rawan Zoabi
- grid.13992.300000 0004 0604 7563Department of Molecular Cell Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Benjamin Cohen
- grid.13992.300000 0004 0604 7563Department of Immunology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Vanessa Drendel
- grid.416008.b0000 0004 0603 4965Department of Pathology, Robert Bosch Hospital, Stuttgart, Germany
| | - Tomer Meir Salame
- grid.13992.300000 0004 0604 7563Flow Cytometry Unit, Department of Life Sciences Core Facilities, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Saptaparna Mukherjee
- grid.13992.300000 0004 0604 7563Department of Molecular Cell Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Nofar Harpaz
- grid.13992.300000 0004 0604 7563Department of Immunology and Regenerative Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Randy Johnson
- grid.240145.60000 0001 2291 4776Department of Cancer Biology, University of Texas MD Anderson Cancer Center, Houston, TX 77030 USA
| | - Walter E. Aulitzky
- grid.416008.b0000 0004 0603 4965Department of Hematology, Oncology and Palliative Medicine, Robert Bosch Hospital, Stuttgart, Germany
| | - Yosef Yarden
- grid.13992.300000 0004 0604 7563Department of Immunology and Regenerative Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Efrat Shema
- grid.13992.300000 0004 0604 7563Department of Immunology and Regenerative Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
| | - Moshe Oren
- grid.13992.300000 0004 0604 7563Department of Molecular Cell Biology, The Weizmann Institute of Science, 76100 Rehovot, Israel
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Quintero J, Saad NY, Pagnoni SM, Jacquelin DK, Gatica LV, Harper SQ, Rosa AL. The DUX4 protein is a co-repressor of the progesterone and glucocorticoid nuclear receptors. FEBS Lett 2022; 596:2644-2658. [PMID: 35662006 DOI: 10.1002/1873-3468.14416] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/24/2022] [Revised: 05/28/2022] [Accepted: 05/28/2022] [Indexed: 11/09/2022]
Abstract
DUX4 is a transcription factor required during early embryonic development in placental mammals. In this work, we provide evidence that DUX4 is a co-repressor of nuclear receptors (NRs) of progesterone (PR) and glucocorticoids (GR). The DUX4 C-ter and N-ter regions, including the nuclear localization signals and homeodomain motifs, contribute to the co-repressor activity of DUX4 on PR and GR. Immunoprecipitation studies, using total protein extracts of cells expressing tagged versions of DUX4 and GR, support that these proteins are physically associated. Our studies suggest that DUX4 could modulate gene expression by co-regulating the activity of hormone NRs. This is the first report highlighting a potential endocrine role for DUX4.
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Affiliation(s)
- Julieta Quintero
- Laboratorio de Genética y Biología Molecular, IRNASUS-CONICET, Facultad de Ciencias Químicas, Universidad Católica de Córdoba, Argentina
| | - Nizar Y Saad
- Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
| | | | - Daniela K Jacquelin
- Laboratorio de Genética y Biología Molecular, IRNASUS-CONICET, Facultad de Ciencias Químicas, Universidad Católica de Córdoba, Argentina
| | - Laura V Gatica
- Laboratorio de Genética y Biología Molecular, IRNASUS-CONICET, Facultad de Ciencias Químicas, Universidad Católica de Córdoba, Argentina
| | - Scott Q Harper
- Center for Gene Therapy, The Research Institute at Nationwide Children's Hospital, Columbus, OH, USA
- Department of Pediatrics, The Ohio State University College of Medicine, Columbus, OH, USA
| | - Alberto L Rosa
- Laboratorio de Genética y Biología Molecular, IRNASUS-CONICET, Facultad de Ciencias Químicas, Universidad Católica de Córdoba, Argentina
- Fundación Allende-CONICET, Córdoba, Argentina
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Jayaprakash S, Hegde M, Girisa S, Alqahtani MS, Abbas M, Lee EHC, Yap KCH, Sethi G, Kumar AP, Kunnumakkara AB. Demystifying the Functional Role of Nuclear Receptors in Esophageal Cancer. Int J Mol Sci 2022; 23:ijms231810952. [PMID: 36142861 PMCID: PMC9501100 DOI: 10.3390/ijms231810952] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/20/2022] [Revised: 09/14/2022] [Accepted: 09/14/2022] [Indexed: 11/16/2022] Open
Abstract
Esophageal cancer (EC), an aggressive and poorly understood disease, is one of the top causes of cancer-related fatalities. GLOBOCAN 2020 reports that there are 544,076 deaths and 604,100 new cases expected worldwide. Even though there are various advancements in treatment procedures, this cancer has been reported as one of the most difficult cancers to cure, and to increase patient survival; treatment targets still need to be established. Nuclear receptors (NRs) are a type of transcription factor, which has a key role in several biological processes such as reproduction, development, cellular differentiation, stress response, immunity, metabolism, lipids, and drugs, and are essential regulators of several diseases, including cancer. Numerous studies have demonstrated the importance of NRs in tumor immunology and proved the well-known roles of multiple NRs in modulating proliferation, differentiation, and apoptosis. There are surplus of studies conducted on NRs and their implications in EC, but only a few studies have demonstrated the diagnostic and prognostic potential of NRs. Therefore, there is still a paucity of the role of NRs and different ways to target them in EC cells to stop them from spreading malignancy. This review emphasizes the significance of NRs in EC by discussing their diverse agonists as well as antagonists and their response to tumor progression. Additionally, we emphasize NRs’ potential to serve as a novel therapeutic target and their capacity to treat and prevent EC.
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Affiliation(s)
- Sujitha Jayaprakash
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India
| | - Mangala Hegde
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India
| | - Sosmitha Girisa
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India
| | - Mohammed S. Alqahtani
- Radiological Sciences Department, College of Applied Medical Sciences, King Khalid University, Abha 61421, Saudi Arabia
- BioImaging Unit, Space Research Centre, Michael Atiyah Building, University of Leicester, Leicester LE1 7RH, UK
| | - Mohamed Abbas
- Electrical Engineering Department, College of Engineering, King Khalid University, Abha 61421, Saudi Arabia
- Electronics and Communications Department, College of Engineering, Delta University for Science and Technology, Gamasa 35712, Egypt
| | - E. Hui Clarissa Lee
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Kenneth Chun-Hong Yap
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Gautam Sethi
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
| | - Alan Prem Kumar
- Department of Pharmacology, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 117600, Singapore
- NUS Center for Cancer Research, Yong Loo Lin School of Medicine, National University of Singapore, Singapore 119228, Singapore
- Correspondence: (A.P.K.); (A.B.K.)
| | - Ajaikumar B. Kunnumakkara
- Cancer Biology Laboratory, Department of Biosciences and Bioengineering, Indian Institute of Technology (IIT) Guwahati, Guwahati 781039, Assam, India
- Correspondence: (A.P.K.); (A.B.K.)
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Gomez RL, Woods LM, Ramachandran R, Abou Tayoun AN, Philpott A, Ali FR. Super-enhancer associated core regulatory circuits mediate susceptibility to retinoic acid in neuroblastoma cells. Front Cell Dev Biol 2022; 10:943924. [PMID: 36147741 PMCID: PMC9485839 DOI: 10.3389/fcell.2022.943924] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/14/2022] [Accepted: 08/08/2022] [Indexed: 11/25/2022] Open
Abstract
Neuroblastoma is a pediatric tumour that accounts for more than 15% of cancer-related deaths in children. High-risk tumours are often difficult to treat, and patients' survival chances are less than 50%. Retinoic acid treatment is part of the maintenance therapy given to neuroblastoma patients; however, not all tumours differentiate in response to retinoic acid. Within neuroblastoma tumors, two phenotypically distinct cell types have been identified based on their super-enhancer landscape and transcriptional core regulatory circuitries: adrenergic (ADRN) and mesenchymal (MES). We hypothesized that the distinct super-enhancers in these different tumour cells mediate differential response to retinoic acid. To this end, three different neuroblastoma cell lines, ADRN (MYCN amplified and non-amplified) and MES cells, were treated with retinoic acid, and changes in the super-enhancer landscape upon treatment and after subsequent removal of retinoic acid was studied. Using ChIP-seq for the active histone mark H3K27ac, paired with RNA-seq, we compared the super-enhancer landscape in cells that undergo neuronal differentiation in response to retinoic acid versus those that fail to differentiate and identified unique super-enhancers associated with neuronal differentiation. Among the ADRN cells that respond to treatment, MYCN-amplified cells remain differentiated upon removal of retinoic acid, whereas MYCN non-amplified cells revert to an undifferentiated state, allowing for the identification of super-enhancers responsible for maintaining differentiation. This study identifies key super-enhancers that are crucial for retinoic acid-mediated differentiation.
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Affiliation(s)
- Roshna Lawrence Gomez
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
| | - Laura M. Woods
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Center, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Department of Oncology, University of Cambridge, Cambridge, United Kingdom
| | - Revathy Ramachandran
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
| | - Ahmad N. Abou Tayoun
- Center for Genomic Discovery, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
- Al Jalila Genomics Center, Al Jalila Children’s Hospital, Dubai, United Arab Emirates
| | - Anna Philpott
- Wellcome-MRC Cambridge Stem Cell Institute, Jeffrey Cheah Biomedical Center, Cambridge Biomedical Campus, Cambridge, United Kingdom
- Department of Oncology, University of Cambridge, Cambridge, United Kingdom
| | - Fahad R. Ali
- College of Medicine, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
- Center for Genomic Discovery, Mohammed Bin Rashid University of Medicine and Health Sciences, Dubai, United Arab Emirates
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The Role of Transcription Factor PPAR-γ in the Pathogenesis of Psoriasis, Skin Cells, and Immune Cells. Int J Mol Sci 2022; 23:ijms23179708. [PMID: 36077103 PMCID: PMC9456565 DOI: 10.3390/ijms23179708] [Citation(s) in RCA: 27] [Impact Index Per Article: 9.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/16/2022] [Revised: 08/22/2022] [Accepted: 08/23/2022] [Indexed: 11/22/2022] Open
Abstract
The peroxisome proliferator-activated receptor PPAR-γ is one of three PPAR nuclear receptors that act as ligand-activated transcription factors. In immune cells, the skin, and other organs, PPAR-γ regulates lipid, glucose, and amino acid metabolism. The receptor translates nutritional, pharmacological, and metabolic stimuli into the changes in gene expression. The activation of PPAR-γ promotes cell differentiation, reduces the proliferation rate, and modulates the immune response. In the skin, PPARs also contribute to the functioning of the skin barrier. Since we know that the route from identification to the registration of drugs is long and expensive, PPAR-γ agonists already approved for other diseases may also represent a high interest for psoriasis. In this review, we discuss the role of PPAR-γ in the activation, differentiation, and proliferation of skin and immune cells affected by psoriasis and in contributing to the pathogenesis of the disease. We also evaluate whether the agonists of PPAR-γ may become one of the therapeutic options to suppress the inflammatory response in lesional psoriatic skin and decrease the influence of comorbidities associated with psoriasis.
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Hess L, Moos V, Lauber AA, Reiter W, Schuster M, Hartl N, Lackner D, Boenke T, Koren A, Guzzardo PM, Gundacker B, Riegler A, Vician P, Miccolo C, Leiter S, Chandrasekharan MB, Vcelkova T, Tanzer A, Jun JQ, Bradner J, Brosch G, Hartl M, Bock C, Bürckstümmer T, Kubicek S, Chiocca S, Bhaskara S, Seiser C. A toolbox for class I HDACs reveals isoform specific roles in gene regulation and protein acetylation. PLoS Genet 2022; 18:e1010376. [PMID: 35994477 PMCID: PMC9436093 DOI: 10.1371/journal.pgen.1010376] [Citation(s) in RCA: 10] [Impact Index Per Article: 3.3] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/22/2021] [Revised: 09/01/2022] [Accepted: 08/06/2022] [Indexed: 02/07/2023] Open
Abstract
The class I histone deacetylases are essential regulators of cell fate decisions in health and disease. While pan- and class-specific HDAC inhibitors are available, these drugs do not allow a comprehensive understanding of individual HDAC function, or the therapeutic potential of isoform-specific targeting. To systematically compare the impact of individual catalytic functions of HDAC1, HDAC2 and HDAC3, we generated human HAP1 cell lines expressing catalytically inactive HDAC enzymes. Using this genetic toolbox we compare the effect of individual HDAC inhibition with the effects of class I specific inhibitors on cell viability, protein acetylation and gene expression. Individual inactivation of HDAC1 or HDAC2 has only mild effects on cell viability, while HDAC3 inactivation or loss results in DNA damage and apoptosis. Inactivation of HDAC1/HDAC2 led to increased acetylation of components of the COREST co-repressor complex, reduced deacetylase activity associated with this complex and derepression of neuronal genes. HDAC3 controls the acetylation of nuclear hormone receptor associated proteins and the expression of nuclear hormone receptor regulated genes. Acetylation of specific histone acetyltransferases and HDACs is sensitive to inactivation of HDAC1/HDAC2. Over a wide range of assays, we determined that in particular HDAC1 or HDAC2 catalytic inactivation mimics class I specific HDAC inhibitors. Importantly, we further demonstrate that catalytic inactivation of HDAC1 or HDAC2 sensitizes cells to specific cancer drugs. In summary, our systematic study revealed isoform-specific roles of HDAC1/2/3 catalytic functions. We suggest that targeted genetic inactivation of particular isoforms effectively mimics pharmacological HDAC inhibition allowing the identification of relevant HDACs as targets for therapeutic intervention.
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Affiliation(s)
- Lena Hess
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Verena Moos
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Arnel A. Lauber
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Wolfgang Reiter
- Mass Spectrometry Core Facility, Max Perutz Labs, Vienna BioCenter, Vienna, Austria
- Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna BioCenter, Vienna, Austria
| | - Michael Schuster
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Natascha Hartl
- Mass Spectrometry Core Facility, Max Perutz Labs, Vienna BioCenter, Vienna, Austria
| | | | - Thorina Boenke
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Anna Koren
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | | | - Brigitte Gundacker
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Anna Riegler
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Petra Vician
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Claudia Miccolo
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Susanna Leiter
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Mahesh B. Chandrasekharan
- Department of Radiation Oncology and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
| | - Terezia Vcelkova
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Andrea Tanzer
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
| | - Jun Qi Jun
- Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
| | - James Bradner
- Dana-Farber Cancer Institute, Boston, Massachusetts, United States of America
| | - Gerald Brosch
- Institute of Molecular Biology, Innsbruck Medical University, Innsbruck, Austria
| | - Markus Hartl
- Mass Spectrometry Core Facility, Max Perutz Labs, Vienna BioCenter, Vienna, Austria
- Department of Biochemistry and Cell Biology, Max Perutz Labs, University of Vienna, Vienna BioCenter, Vienna, Austria
| | - Christoph Bock
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
- Institute of Artificial Intelligence, Center for Medical Statistics, Informatics, and Intelligent Systems, Medical University of Vienna, Vienna, Austria
| | | | - Stefan Kubicek
- CeMM Research Center for Molecular Medicine of the Austrian Academy of Sciences, Vienna, Austria
| | - Susanna Chiocca
- Department of Experimental Oncology, IEO, European Institute of Oncology IRCCS, Milan, Italy
| | - Srividya Bhaskara
- Department of Radiation Oncology and Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, Utah, United States of America
| | - Christian Seiser
- Center for Anatomy and Cell Biology, Medical University of Vienna, Vienna, Austria
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Yao B, Yang C, Pan C, Li Y. Thyroid hormone resistance: Mechanisms and therapeutic development. Mol Cell Endocrinol 2022; 553:111679. [PMID: 35738449 DOI: 10.1016/j.mce.2022.111679] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/09/2020] [Revised: 05/03/2021] [Accepted: 05/09/2022] [Indexed: 10/18/2022]
Abstract
As an essential primary hormone, thyroid hormone (TH) is indispensable for human growth, development and metabolism. Impairment of TH function in several aspects, including TH synthesis, activation, transportation and receptor-dependent transactivation, can eventually lead to thyroid hormone resistance syndrome (RTH). RTH is a rare syndrome that manifests as a reduced target cell response to TH signaling. The majority of RTH cases are related to thyroid hormone receptor β (TRβ) mutations, and only a few RTH cases are associated with thyroid hormone receptor α (TRα) mutations or other causes. Patients with RTH suffer from goiter, mental retardation, short stature and bradycardia or tachycardia. To date, approximately 170 mutated TRβ variants and more than 20 mutated TRα variants at the amino acid level have been reported in RTH patients. In addition to these mutated proteins, some TR isoforms can also reduce TH function by competing with primary TRs for TRE and RXR binding. Fortunately, different treatments for RTH have been explored with structure-activity relationship (SAR) studies and drug design, and among these treatments. With thyromimetic potency but biochemical properties that differ from those of primary TH (T3 and T4), these TH analogs can bypass specific defective transporters or reactive mutant TRs. However, these compounds must be carefully applied to avoid over activating TRα, which is associated with more severe heart impairment. The structural mechanisms of mutation-induced RTH in the TR ligand-binding domain are summarized in this review. Furthermore, strategies to overcome this resistance for therapeutic development are also discussed.
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Affiliation(s)
- Benqiang Yao
- The State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian, 361005, China
| | - Chunyan Yang
- The State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian, 361005, China.
| | - Chengxi Pan
- The State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian, 361005, China
| | - Yong Li
- The State Key Laboratory of Cellular Stress Biology, Innovation Center for Cell Signaling Network, School of Life Sciences, Xiamen University, Fujian, 361005, China.
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Yoo HS, Rodriguez A, You D, Lee RA, Cockrum MA, Grimes JA, Wang JC, Kang S, Napoli JL. The glucocorticoid receptor represses, whereas C/EBPβ can enhance or repress CYP26A1 transcription. iScience 2022; 25:104564. [PMID: 35789854 PMCID: PMC9249609 DOI: 10.1016/j.isci.2022.104564] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/19/2021] [Revised: 05/12/2022] [Accepted: 06/06/2022] [Indexed: 11/24/2022] Open
Abstract
Retinoic acid (RA) counters insulin's metabolic actions. Insulin reduces liver RA biosynthesis by exporting FoxO1 from nuclei. RA induces its catabolism, catalyzed by CYP26A1. A CYP26A1 contribution to RA homeostasis with changes in energy status had not been investigated. We found that glucagon, cortisol, and dexamethasone decrease RA-induced CYP26A1 transcription, thereby reducing RA oxidation during fasting. Interaction between the glucocorticoid receptor and the RAR/RXR coactivation complex suppresses CYP26A1 expression, increasing RA's elimination half-life. Interaction between CCAAT-enhancer-binding protein beta (C/EBPβ) and the major allele of SNP rs2068888 enhances CYP26A1 expression; the minor allele restricts the C/EBPβ effect on CYP26A1. The major and minor alleles associate with impaired human health or reduction in blood triglycerides, respectively. Thus, regulating CYP26A1 transcription contributes to adapting RA to coordinate energy availability with metabolism. These results enhance insight into CYP26A1 effects on RA during changes in energy status and glucocorticoid receptor modification of RAR-regulated gene expression.
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Affiliation(s)
- Hong Sik Yoo
- Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, The University of California, Berkeley Berkeley, CA 94720, USA
| | - Adrienne Rodriguez
- Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, The University of California, Berkeley Berkeley, CA 94720, USA
| | - Dongjoo You
- Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, The University of California, Berkeley Berkeley, CA 94720, USA
| | - Rebecca A. Lee
- Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, The University of California, Berkeley Berkeley, CA 94720, USA
| | - Michael A. Cockrum
- Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, The University of California, Berkeley Berkeley, CA 94720, USA
| | - Jack A. Grimes
- Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, The University of California, Berkeley Berkeley, CA 94720, USA
| | - Jen-Chywan Wang
- Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, The University of California, Berkeley Berkeley, CA 94720, USA
| | - Sona Kang
- Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, The University of California, Berkeley Berkeley, CA 94720, USA
| | - Joseph L. Napoli
- Department of Nutritional Sciences and Toxicology, Graduate Program in Metabolic Biology, The University of California, Berkeley Berkeley, CA 94720, USA
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Akter R, Afrose A, Sharmin S, Rezwan R, Rahman MR, Neelotpol S. A comprehensive look into the association of vitamin D levels and vitamin D receptor gene polymorphism with obesity in children. Biomed Pharmacother 2022; 153:113285. [PMID: 35728355 DOI: 10.1016/j.biopha.2022.113285] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2022] [Revised: 05/27/2022] [Accepted: 06/09/2022] [Indexed: 11/02/2022] Open
Abstract
Childhood obesity accounts for several psychosocial and clinical consequences. Psychosocial consequences include lower self-esteem, social isolation, poor academic achievement, peer problems, and depression, whereas clinical consequences are cardiovascular diseases, type 2 diabetes, dyslipidemia, cancer, autoimmune diseases, girls early polycystic ovarian syndrome (PCOS), asthma, bone deformities, etc. A growing number of studies have uncovered the association of childhood obesity and its consequences with vitamin-D (vit-D) deficiency and vitamin-D receptor (VDR) gene polymorphisms such as single nucleotide polymorphisms (SNPs), e.g., TaqI, BsmI, ApaI, FokI, and Cdx2. Considering the impact of vit-D deficiency and VDR gene polymorphisms, identifying associated factors and risk groups linked to lower serum vit-D levels and prevention of obesity-related syndromes in children is of utmost importance. Previously published review articles mainly focused on the association of vit-D deficiency with obesity or other non-communicable diseases in children. The nature of the correlation between vit-D deficiency and VDR gene polymorphisms with obesity in children is yet to be clarified. Therefore, this review attempts to delineate the association of obesity with these two factors by identifying the molecular mechanism of the relationship.
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Affiliation(s)
- Raushanara Akter
- School of Pharmacy, Brac University, 66 Mohakhali, Dhaka, Bangladesh
| | - Afrina Afrose
- School of Pharmacy, Brac University, 66 Mohakhali, Dhaka, Bangladesh
| | - Shahana Sharmin
- School of Pharmacy, Brac University, 66 Mohakhali, Dhaka, Bangladesh
| | - Rifat Rezwan
- School of Pharmacy, Brac University, 66 Mohakhali, Dhaka, Bangladesh
| | - Md Rashidur Rahman
- Department of Pharmacy, Jashore University of Science and Technology, Jashore 7408, Bangladesh
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Jafari H, Hussain S, Campbell MJ. Nuclear Receptor Coregulators in Hormone-Dependent Cancers. Cancers (Basel) 2022; 14:2402. [PMID: 35626007 PMCID: PMC9139824 DOI: 10.3390/cancers14102402] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/29/2022] [Accepted: 05/09/2022] [Indexed: 12/10/2022] Open
Abstract
Nuclear receptors (NRs) function collectively as a transcriptional signaling network that mediates gene regulatory actions to either maintain cellular homeostasis in response to hormonal, dietary and other environmental factors, or act as orphan receptors with no known ligand. NR complexes are large and interact with multiple protein partners, collectively termed coregulators. Coregulators are essential for regulating NR activity and can dictate whether a target gene is activated or repressed by a variety of mechanisms including the regulation of chromatin accessibility. Altered expression of coregulators contributes to a variety of hormone-dependent cancers including breast and prostate cancers. Therefore, understanding the mechanisms by which coregulators interact with and modulate the activity of NRs provides opportunities to develop better prognostic and diagnostic approaches, as well as novel therapeutic targets. This review aims to gather and summarize recent studies, techniques and bioinformatics methods used to identify distorted NR coregulator interactions that contribute as cancer drivers in hormone-dependent cancers.
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Affiliation(s)
- Hedieh Jafari
- Department of Molecular Genetics, The Ohio State University, Columbus, OH 43210, USA;
- Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA;
| | - Shahid Hussain
- Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA;
| | - Moray J. Campbell
- Department of Pharmaceutics and Pharmaceutical Chemistry, College of Pharmacy, The Ohio State University, Columbus, OH 43210, USA;
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Kuehner F, Stubenrauch F. Functions of Papillomavirus E8^E2 Proteins in Tissue Culture and In Vivo. Viruses 2022; 14:v14050953. [PMID: 35632695 PMCID: PMC9143700 DOI: 10.3390/v14050953] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/22/2022] [Revised: 04/25/2022] [Accepted: 04/29/2022] [Indexed: 12/04/2022] Open
Abstract
Papillomaviruses (PV) replicate in undifferentiated keratinocytes at low levels and to high levels in differentiated cells. The restricted replication in undifferentiated cells is mainly due to the expression of the conserved viral E8^E2 repressor protein, a fusion protein consisting of E8 and the hinge, DNA-binding, and dimerization domain of E2. E8^E2 binds to viral genomes and represses viral transcription and genome replication by recruiting cellular NCoR/SMRT-HDAC3 corepressor complexes. Tissue culture experiments have revealed that E8^E2 modulates long-term maintenance of extrachromosomal genomes, productive replication, and immortalization properties in a virus type-dependent manner. Furthermore, in vivo experiments have indicated that Mus musculus PV1 E8^E2 is required for tumor formation in immune-deficient mice. In summary, E8^E2 is a crucial inhibitor whose levels might determine the outcome of PV infections.
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Lu X, Fong KW, Gritsina G, Wang F, Baca SC, Brea LT, Berchuck JE, Spisak S, Ross J, Morrissey C, Corey E, Chandel NS, Catalona WJ, Yang X, Freedman ML, Zhao JC, Yu J. HOXB13 suppresses de novo lipogenesis through HDAC3-mediated epigenetic reprogramming in prostate cancer. Nat Genet 2022; 54:670-683. [PMID: 35468964 PMCID: PMC9117466 DOI: 10.1038/s41588-022-01045-8] [Citation(s) in RCA: 50] [Impact Index Per Article: 16.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/26/2020] [Accepted: 02/28/2022] [Indexed: 01/16/2023]
Abstract
HOXB13, a homeodomain transcription factor, critically regulates androgen receptor (AR) activities and androgen-dependent prostate cancer (PCa) growth. However, its functions in AR-independent contexts remain elusive. Here we report HOXB13 interaction with histone deacetylase HDAC3, which is disrupted by the HOXB13 G84E mutation that has been associated with early-onset PCa. Independently of AR, HOXB13 recruits HDAC3 to lipogenic enhancers to catalyze histone deacetylation and suppress lipogenic regulators such as fatty acid synthase. Analysis of human tissues reveals that the HOXB13 gene is hypermethylated and downregulated in approximately 30% of metastatic castration-resistant PCa. HOXB13 loss or G84E mutation leads to lipid accumulation in PCa cells, thereby promoting cell motility and xenograft tumor metastasis, which is mitigated by pharmaceutical inhibition of fatty acid synthase. In summary, we present evidence that HOXB13 recruits HDAC3 to suppress de novo lipogenesis and inhibit tumor metastasis and that lipogenic pathway inhibitors may be useful to treat HOXB13-low PCa.
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Affiliation(s)
- Xiaodong Lu
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Ka-wing Fong
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Galina Gritsina
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Fang Wang
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Sylvan C. Baca
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Lourdes T. Brea
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA
| | - Jacob E. Berchuck
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Sandor Spisak
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jenny Ross
- Department of Pathology, Northwestern University, Chicago, IL, USA
| | - Colm Morrissey
- Department of Urology, University of Washington, Seattle, USA
| | - Eva Corey
- Department of Urology, University of Washington, Seattle, USA
| | - Navdeep S. Chandel
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA,Division of Pulmonary and Critical Care, Department of Medicine, Northwestern University, Chicago, IL, USA,Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA
| | - William J. Catalona
- Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA,Department of Urology, Northwestern University, Chicago, IL, USA
| | - Ximing Yang
- Department of Pathology, Northwestern University, Chicago, IL, USA,Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA
| | - Matthew L. Freedman
- Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA,Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Boston, MA, USA
| | - Jonathan C. Zhao
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA,Co-Corresponding Authors: Jindan Yu, M.D., Ph.D. , Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine; Jonathan C. Zhao,
| | - Jindan Yu
- Division of Hematology/Oncology, Department of Medicine, Northwestern University Feinberg School of Medicine, Chicago, IL, USA,Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Chicago, IL, USA,Department of Biochemistry and Molecular Genetics, Northwestern University, Chicago, IL, USA,Co-Corresponding Authors: Jindan Yu, M.D., Ph.D. , Division of Hematology/Oncology, Department of Medicine, Robert H. Lurie Comprehensive Cancer Center, Northwestern University, Feinberg School of Medicine; Jonathan C. Zhao,
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Bos A, van Egmond M, Mebius R. The role of retinoic acid in the production of immunoglobulin A. Mucosal Immunol 2022; 15:562-572. [PMID: 35418672 DOI: 10.1038/s41385-022-00509-8] [Citation(s) in RCA: 19] [Impact Index Per Article: 6.3] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/21/2021] [Revised: 03/09/2022] [Accepted: 03/26/2022] [Indexed: 02/04/2023]
Abstract
Vitamin A and its derivative retinoic acid (RA) play important roles in the regulation of mucosal immunity. The effect of vitamin A metabolism on T lymphocyte immunity has been well documented, but its role in mucosal B lymphocyte regulation is less well described. Intestinal immunoglobulin A (IgA) is key in orchestrating a balanced gut microbiota composition. Here, we describe the contribution of RA to IgA class switching in tissues including the lamina propria, mesenteric lymph nodes, Peyer's patches and isolated lymphoid follicles. RA can either indirectly skew T cells or directly affect B cell differentiation. IgA levels in healthy individuals are under the control of the metabolism of vitamin A, providing a steady supply of RA. However, IgA levels are altered in inflammatory bowel disease patients, making control of the metabolism of vitamin A a potential therapeutic target. Thus, dietary vitamin A is a key player in regulating IgA production within the intestine, acting via multiple immunological pathways.
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Affiliation(s)
- Amelie Bos
- Amsterdam UMC, Department of Molecular Cell Biology and Immunology, Research Institute of Amsterdam Institute for Infection and Immunity, Vrije Universiteit, Amsterdam, The Netherlands
| | - Marjolein van Egmond
- Amsterdam UMC, Department of Molecular Cell Biology and Immunology, Research Institute of Amsterdam Institute for Infection and Immunity, Vrije Universiteit, Amsterdam, The Netherlands.,Amsterdam UMC, Department of Surgery, Research Institute of Amsterdam Institute for Infection and Immunity, Vrije Universiteit, Amsterdam, The Netherlands
| | - Reina Mebius
- Amsterdam UMC, Department of Molecular Cell Biology and Immunology, Research Institute of Amsterdam Institute for Infection and Immunity, Vrije Universiteit, Amsterdam, The Netherlands.
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Juvenile hormone-induced histone deacetylase 3 suppresses apoptosis to maintain larval midgut in the yellow fever mosquito. Proc Natl Acad Sci U S A 2022; 119:e2118871119. [PMID: 35259020 PMCID: PMC8931318 DOI: 10.1073/pnas.2118871119] [Citation(s) in RCA: 11] [Impact Index Per Article: 3.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/22/2023] Open
Abstract
SignificanceJuvenile hormone (JH), a sesquiterpenoid, regulates many aspects of insect development, including maintenance of the larval stage by preventing metamorphosis. In contrast, ecdysteroids promote metamorphosis by inducing the E93 transcription factor, which triggers apoptosis of larval cells and remodeling of the larval midgut. We discovered that JH suppresses precocious larval midgut-remodeling by inducing an epigenetic modifier, histone deacetylase 3 (HDAC3). JH-induced HDAC3 deacetylates the histone H4 localized at the promoters of proapoptotic genes, resulting in the suppression of these genes. This eventually prevents programmed cell death of midgut cells and midgut-remodeling during larval stages. These studies identified a previously unknown mechanism of JH action in blocking premature remodeling of the midgut during larval feeding stages.
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Krivdova G, Voisin V, Schoof EM, Marhon SA, Murison A, McLeod JL, Gabra MM, Zeng AGX, Aigner S, Yee BA, Shishkin AA, Van Nostrand EL, Hermans KG, Trotman-Grant AC, Mbong N, Kennedy JA, Gan OI, Wagenblast E, De Carvalho DD, Salmena L, Minden MD, Bader GD, Yeo GW, Dick JE, Lechman ER. Identification of the global miR-130a targetome reveals a role for TBL1XR1 in hematopoietic stem cell self-renewal and t(8;21) AML. Cell Rep 2022; 38:110481. [PMID: 35263585 PMCID: PMC11185845 DOI: 10.1016/j.celrep.2022.110481] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/09/2021] [Revised: 12/03/2021] [Accepted: 02/11/2022] [Indexed: 11/18/2022] Open
Abstract
Gene expression profiling and proteome analysis of normal and malignant hematopoietic stem cells (HSCs) point to shared core stemness properties. However, discordance between mRNA and protein signatures highlights an important role for post-transcriptional regulation by microRNAs (miRNAs) in governing this critical nexus. Here, we identify miR-130a as a regulator of HSC self-renewal and differentiation. Enforced expression of miR-130a impairs B lymphoid differentiation and expands long-term HSCs. Integration of protein mass spectrometry and chimeric AGO2 crosslinking and immunoprecipitation (CLIP) identifies TBL1XR1 as a primary miR-130a target, whose loss of function phenocopies miR-130a overexpression. Moreover, we report that miR-130a is highly expressed in t(8;21) acute myeloid leukemia (AML), where it is critical for maintaining the oncogenic molecular program mediated by the AML1-ETO complex. Our study establishes that identification of the comprehensive miRNA targetome within primary cells enables discovery of genes and molecular networks underpinning stemness properties of normal and leukemic cells.
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Affiliation(s)
- Gabriela Krivdova
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A5, Canada
| | - Veronique Voisin
- The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada
| | - Erwin M Schoof
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Sajid A Marhon
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Alex Murison
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Jessica L McLeod
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Martino M Gabra
- Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Andy G X Zeng
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A5, Canada
| | - Stefan Aigner
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA
| | - Brian A Yee
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA
| | - Alexander A Shishkin
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA
| | - Eric L Van Nostrand
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA
| | - Karin G Hermans
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Program of Developmental & Stem Cell Biology, Peter Gilgan Centre for Research and Learning, The Hospital for Sick Children, Toronto, ON M5G0A4, Canada
| | - Aaron C Trotman-Grant
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Nathan Mbong
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
| | - James A Kennedy
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Division of Medical Oncology and Hematology, Sunnybrook Health Sciences Centre, Toronto, ON M4N3M5, Canada
| | - Olga I Gan
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Elvin Wagenblast
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Daniel D De Carvalho
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Medical Biophysics, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Leonardo Salmena
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Pharmacology and Toxicology, University of Toronto, Toronto, ON M5S 1A8, Canada
| | - Mark D Minden
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada
| | - Gary D Bader
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A5, Canada; The Donnelly Centre, University of Toronto, Toronto, ON M5S 3E1, Canada; Department of Computer Science, University of Toronto, Toronto, ON M5T 3A1, Canada
| | - Gene W Yeo
- Department of Cellular and Molecular Medicine, University of California, San Diego, La Jolla, CA 92037, USA
| | - John E Dick
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada; Department of Molecular Genetics, University of Toronto, Toronto, ON M5S1A5, Canada.
| | - Eric R Lechman
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 1L7, Canada.
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50
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Gangwar SK, Kumar A, Jose S, Alqahtani MS, Abbas M, Sethi G, Kunnumakkara AB. Nuclear receptors in oral cancer-emerging players in tumorigenesis. Cancer Lett 2022; 536:215666. [DOI: 10.1016/j.canlet.2022.215666] [Citation(s) in RCA: 3] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/20/2022] [Revised: 03/25/2022] [Accepted: 03/25/2022] [Indexed: 12/24/2022]
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