|
1
|
Lisek M, Tomczak J, Swiatek J, Kaluza A, Boczek T. Histone Deacetylases in Retinoblastoma. Int J Mol Sci 2024; 25:6910. [PMID: 39000021 PMCID: PMC11241206 DOI: 10.3390/ijms25136910] [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: 04/30/2024] [Revised: 06/16/2024] [Accepted: 06/19/2024] [Indexed: 07/14/2024] Open
Abstract
Retinoblastoma, a pediatric ocular malignancy, presents significant challenges in comprehending its molecular underpinnings and targeted therapeutic approaches. The dysregulated activity of histone deacetylases (HDACs) has been associated with retinoblastoma pathogenesis, influencing critical cellular processes like cell cycle regulation or retinal ganglion cell apoptosis. Through their deacetylase activity, HDACs exert control over key tumor suppressors and oncogenes, influencing the delicate equilibrium between proliferation and cell death. Furthermore, the interplay between HDACs and the retinoblastoma protein pathway, a pivotal aspect of retinoblastoma etiology, reveals a complex network of interactions influencing the tumor microenvironment. The examination of HDAC inhibitors, encompassing both established and novel compounds, offers insights into potential approaches to restore acetylation balance and impede retinoblastoma progression. Moreover, the identification of specific HDAC isoforms exhibiting varying expression in retinoblastoma provides avenues for personalized therapeutic strategies, allowing for interventions tailored to individual patient profiles. This review focuses on the intricate interrelationship between HDACs and retinoblastoma, shedding light on epigenetic mechanisms that control tumor development and progression. The exploration of HDAC-targeted therapies underscores the potential for innovative treatment modalities in the pursuit of more efficacious and personalized management strategies for this disease.
Collapse
Affiliation(s)
- Malwina Lisek
- Department of Molecular Neurochemistry, Medical University of Lodz, 90-419 Lodz, Poland; (J.T.); (J.S.); (A.K.)
| | | | | | | | - Tomasz Boczek
- Department of Molecular Neurochemistry, Medical University of Lodz, 90-419 Lodz, Poland; (J.T.); (J.S.); (A.K.)
| |
Collapse
|
|
2
|
Subramani PG, Fraszczak J, Helness A, Estall JL, Möröy T, Di Noia JM. Conserved role of hnRNPL in alternative splicing of epigenetic modifiers enables B cell activation. EMBO Rep 2024; 25:2662-2697. [PMID: 38744970 PMCID: PMC11169469 DOI: 10.1038/s44319-024-00152-3] [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: 10/05/2023] [Revised: 04/15/2024] [Accepted: 04/24/2024] [Indexed: 05/16/2024] Open
Abstract
The multifunctional RNA-binding protein hnRNPL is implicated in antibody class switching but its broader function in B cells is unknown. Here, we show that hnRNPL is essential for B cell activation, germinal center formation, and antibody responses. Upon activation, hnRNPL-deficient B cells show proliferation defects and increased apoptosis. Comparative analysis of RNA-seq data from activated B cells and another eight hnRNPL-depleted cell types reveals common effects on MYC and E2F transcriptional programs required for proliferation. Notably, while individual gene expression changes are cell type specific, several alternative splicing events affecting histone modifiers like KDM6A and SIRT1, are conserved across cell types. Moreover, hnRNPL-deficient B cells show global changes in H3K27me3 and H3K9ac. Epigenetic dysregulation after hnRNPL loss could underlie differential gene expression and upregulation of lncRNAs, and explain common and cell type-specific phenotypes, such as dysfunctional mitochondria and ROS overproduction in mouse B cells. Thus, hnRNPL is essential for the resting-to-activated B cell transition by regulating transcriptional programs and metabolism, at least in part through the alternative splicing of several histone modifiers.
Collapse
Affiliation(s)
- Poorani Ganesh Subramani
- Institut de Recherches Cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada
- Department of Medicine, Division of Experimental Medicine, McGill University, 1001 Boulevard Decarie, Montreal, QC, H4A 3J1, Canada
| | - Jennifer Fraszczak
- Institut de Recherches Cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada
| | - Anne Helness
- Institut de Recherches Cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada
| | - Jennifer L Estall
- Institut de Recherches Cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada
- Department of Medicine, Division of Experimental Medicine, McGill University, 1001 Boulevard Decarie, Montreal, QC, H4A 3J1, Canada
- Molecular Biology Programs, Université de Montréal, C.P. 6128, succ. Centre-ville, Montréal, QC, H3C 3J7, Canada
- Department of Medicine, Université de Montréal, C.P. 6128, succ. Centre-ville, Montréal, QC, H3C 3J7, Canada
| | - Tarik Möröy
- Institut de Recherches Cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada
- Department of Medicine, Division of Experimental Medicine, McGill University, 1001 Boulevard Decarie, Montreal, QC, H4A 3J1, Canada
- Molecular Biology Programs, Université de Montréal, C.P. 6128, succ. Centre-ville, Montréal, QC, H3C 3J7, Canada
- Département de microbiologie, infectiologie et immunologie, Université de Montréal, 2900 Boul Edouard-Montpetit, Montréal, QC, H3T 1J4, Canada
| | - Javier M Di Noia
- Institut de Recherches Cliniques de Montréal, 110 avenue des Pins Ouest, Montréal, QC, H2W 1R7, Canada.
- Department of Medicine, Division of Experimental Medicine, McGill University, 1001 Boulevard Decarie, Montreal, QC, H4A 3J1, Canada.
- Molecular Biology Programs, Université de Montréal, C.P. 6128, succ. Centre-ville, Montréal, QC, H3C 3J7, Canada.
- Department of Medicine, Université de Montréal, C.P. 6128, succ. Centre-ville, Montréal, QC, H3C 3J7, Canada.
- Département de microbiologie, infectiologie et immunologie, Université de Montréal, 2900 Boul Edouard-Montpetit, Montréal, QC, H3T 1J4, Canada.
| |
Collapse
|
|
3
|
Abate M, Lombardi A, Luce A, Porru M, Leonetti C, Bocchetti M, Campani V, De Rosa G, Graziano SF, Nele V, Cardile F, Marino FZ, Franco R, Ronchi A, Scrima M, Sperlongano R, Alfano R, Misso G, Amler E, Caraglia M, Zappavigna S. Fluorescent nanodiamonds as innovative delivery systems for MiR-34a replacement in breast cancer. MOLECULAR THERAPY. NUCLEIC ACIDS 2023; 33:127-141. [PMID: 37449042 PMCID: PMC10336355 DOI: 10.1016/j.omtn.2023.06.012] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 04/06/2023] [Accepted: 06/14/2023] [Indexed: 07/18/2023]
Abstract
Nanodiamonds are innovative nanocrystalline carbon particles able to deliver chemically conjugated miRNAs. In oncology, the use of miRNA-based therapies may represent an advantage, based on their ability to simultaneously target multiple intracellular oncogenic targets. Here, nanodiamonds were tested and optimized to deliver miR-34a, a miRNA playing a key role in inhibiting tumor development and progression in many cancers. The physical-chemical properties of nanodiamonds were investigated suggesting electrical stability and uniformity of structure and size. Moreover, we evaluated nanodiamond cytotoxicity on two breast cancer cell models and confirmed their excellent biocompatibility. Subsequently, nanodiamonds were conjugated with miR-34a, using the chemical crosslinker polyethyleneimine; real-time PCR analysis revealed a higher level of miR-34a in cancer cells treated with the different formulations of nanodiamonds than with commercial transfectant. A significant and early nanodiamond-miR-34a uptake was recorded by FACS and fluorescence microscopy analysis in MCF7 and MDA-MB-231 cells. Moreover, nanodiamond-miR-34a significantly inhibited both cell proliferation and migration. Finally, a remarkable anti-tumor effect of miR-34a-conjugated nanodiamonds was observed in both heterotopic and orthotopic murine xenograft models. In conclusion, this study provides a rationale for the development of new therapeutic strategies based on use of miR-34a delivered by nanodiamonds to improve the clinical treatment of neoplasms.
Collapse
Affiliation(s)
- Marianna Abate
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli,” Via L. De Crecchio 7, 80138 Naples, Italy
- Institute of Biophysics, 2nd Faculty of Medicine, Charles University, V Uvalu 84, 15006 Prague, Czech Republic
| | - Angela Lombardi
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli,” Via L. De Crecchio 7, 80138 Naples, Italy
| | - Amalia Luce
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli,” Via L. De Crecchio 7, 80138 Naples, Italy
| | - Manuela Porru
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, E Chianesi 53, 00144 Rome, Italy
| | - Carlo Leonetti
- Translational Oncology Research Unit, IRCCS Regina Elena National Cancer Institute, E Chianesi 53, 00144 Rome, Italy
| | - Marco Bocchetti
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli,” Via L. De Crecchio 7, 80138 Naples, Italy
- Laboratory of Precision and Molecular Oncology, Biogem Scarl, Institute of Genetic Research, Contrada Camporeale, 83031 Ariano Irpino, Italy
| | - Virginia Campani
- Department of Pharmacy, University of Naples Federico II, D. Montesano 49, 80131 Naples, Italy
| | - Giuseppe De Rosa
- Department of Pharmacy, University of Naples Federico II, D. Montesano 49, 80131 Naples, Italy
| | - Sossio Fabio Graziano
- Department of Pharmacy, University of Naples Federico II, D. Montesano 49, 80131 Naples, Italy
| | - Valeria Nele
- Department of Pharmacy, University of Naples Federico II, D. Montesano 49, 80131 Naples, Italy
| | - Francesco Cardile
- Laboratory of Precision and Molecular Oncology, Biogem Scarl, Institute of Genetic Research, Contrada Camporeale, 83031 Ariano Irpino, Italy
| | - Federica Zito Marino
- Department of Mental and Physical Health and Preventive Medicine, Pathology Unit, University of Campania “Luigi Vanvitelli,” 80138 Naples, Italy
| | - Renato Franco
- Department of Mental and Physical Health and Preventive Medicine, Pathology Unit, University of Campania “Luigi Vanvitelli,” 80138 Naples, Italy
| | - Andrea Ronchi
- Department of Mental and Physical Health and Preventive Medicine, Pathology Unit, University of Campania “Luigi Vanvitelli,” 80138 Naples, Italy
| | - Marianna Scrima
- Laboratory of Precision and Molecular Oncology, Biogem Scarl, Institute of Genetic Research, Contrada Camporeale, 83031 Ariano Irpino, Italy
| | - Rossella Sperlongano
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli,” Via L. De Crecchio 7, 80138 Naples, Italy
| | - Roberto Alfano
- Department of Advanced Medical and Surgical Sciences “DAMSS,” University of Campania “Luigi Vanvitelli,” Via S. M. di Costantinopoli 104, 80138 Naples, Italy
| | - Gabriella Misso
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli,” Via L. De Crecchio 7, 80138 Naples, Italy
| | - Evzen Amler
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli,” Via L. De Crecchio 7, 80138 Naples, Italy
- Institute of Biophysics, 2nd Faculty of Medicine, Charles University, V Uvalu 84, 15006 Prague, Czech Republic
| | - Michele Caraglia
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli,” Via L. De Crecchio 7, 80138 Naples, Italy
- Laboratory of Precision and Molecular Oncology, Biogem Scarl, Institute of Genetic Research, Contrada Camporeale, 83031 Ariano Irpino, Italy
| | - Silvia Zappavigna
- Department of Precision Medicine, University of Campania “Luigi Vanvitelli,” Via L. De Crecchio 7, 80138 Naples, Italy
| |
Collapse
|
|
4
|
Dang F, Wei W. Targeting the acetylation signaling pathway in cancer therapy. Semin Cancer Biol 2022; 85:209-218. [PMID: 33705871 PMCID: PMC8423867 DOI: 10.1016/j.semcancer.2021.03.001] [Citation(s) in RCA: 38] [Impact Index Per Article: 12.7] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/31/2021] [Revised: 02/22/2021] [Accepted: 03/02/2021] [Indexed: 12/12/2022]
Abstract
Acetylation represents one of the major post-translational protein modifications, which introduces an acetyl functional group into amino acids such as the lysine residue to yield an acetate ester bond, neutralizing its positive charge. Regulation of protein functions by acetylation occurs in multiple ways, such as affecting protein stability, activity, localization, and interaction with other proteins or DNA. It has been well documented that the recruitment of histone acetyltransferases (HATs) and histone deacetylases (HDACs) to the transcriptional machinery can modulate histone acetylation status, which is directly involved in the dynamic regulation of genes controlling cell proliferation and division. Dysregulation of gene expression is involved in tumorigenesis and aberrant activation of histone deacetylases has been reported in several types of cancer. Moreover, there is growing body of evidence showing that acetylation is widely involved in non-histone proteins to impact their roles in various cellular processes including tumorigenesis. As such, small molecular compounds inhibiting HAT or HDAC enzymatic activities have been developed and investigated for therapeutic purpose. Here we review the recent progress in our understanding of protein acetylation and discuss the therapeutic potential of targeting the acetylation signaling pathway in cancer.
Collapse
Affiliation(s)
- Fabin Dang
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA
| | - Wenyi Wei
- Department of Pathology, Beth Israel Deaconess Medical Center, Harvard Medical School, Boston, MA, 02215, USA.
| |
Collapse
|
|
5
|
Nucleolar protein NOC4L inhibits tumorigenesis and progression by attenuating SIRT1-mediated p53 deacetylation. Oncogene 2022; 41:4474-4484. [PMID: 36030331 DOI: 10.1038/s41388-022-02447-y] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/27/2021] [Revised: 08/11/2022] [Accepted: 08/16/2022] [Indexed: 11/08/2022]
Abstract
SIRT1 is an NAD+-dependent deacetylase and plays an important role in the deacetylation of both histone and non-histone proteins. Many studies revealed that SIRT1 is upregulated in a variety of tumors and tightly associated with tumorigenesis and cancer progression, but the detailed underlying mechanism of the biological processes remains unclarified. In the present study, we found a nucleolar protein NOC4L, human ortholog of yeast Noc4p, which is essential for the nuclear export of the ribosomal 40S subunit and could bind to SIRT1 to inhibit SIRT1 mediated deacetylation of p53. NOC4L interacts with SIRT1 in variety of cells under nucleolar stress and directly interacts with SIRT1 in vitro. Furthermore, we determined the C-terminal of NOC4L and the catalytic domain of SIRT1 were required for their interaction. Overexpression of NOC4L did not change the protein levels of SIRT1 or p53, but increased the acetylation of p53 and promoted cell apoptosis. Additionally, NOC4L inhibited tumor cell proliferation in a p53-dependent manner and restrained tumor growth in a nude mice xenograft model. Clinically, colorectal cancer patients with the high expression of NOC4L had a better prognosis as TP53 was normally expressed, but no significant difference was observed in survival with mutant TP53. Taken together, our results identified a novel SIRT1 regulatory protein and broaden our understanding of the molecular mechanism of how nucleolar protein NOC4L regulates p53 under nucleolar stress. This research provides an insight into tumorigenesis and cell self-protection in the early stage of DNA damage.
Collapse
|
|
6
|
Huang J, Zhang F, Hu G, Pan Y, Sun W, Jiang L, Wang P, Qiu J, Ding X. SIRT1 suppresses pituitary tumor progression by downregulating PTTG1 expression. Oncol Rep 2022; 48:143. [PMID: 35730625 DOI: 10.3892/or.2022.8354] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/03/2021] [Accepted: 01/03/2022] [Indexed: 11/06/2022] Open
Abstract
Although pituitary tumors are among the most common types of brain tumor, the underlying molecular mechanism of this disease remains obscure. To this end, the role of sirtuin 1 (SIRT1) in pituitary tumors was reported. The results of reverse transcription‑quantitative PCR and immunohistochemistry revealed that sirtuin 1 (SIRT1) expression was downregulated in the tumor tissues of patients with pituitary tumors. In vitro experiments of the present study demonstrated that SIRT1 upregulation suppressed pituitary tumor cell line growth, while SIRT1 downregulation demonstrated the opposite effect. Additionally, it was determined that the enzymatic activity of SIRT1 was required for its cellular function. A mechanistic experiment determined that SIRT1 negatively regulated pituitary tumor‑transforming gene 1 (PTTG1) expression through the deacetylation of histone (H)3 lysine (K)9ac at the promoter region of PTTG1. Moreover, H3K9ac levels at the PTTG1 promoter were determined to be an essential regulatory element for PTTG1 expression. Thus, it was concluded that the SIRT1/H3K9ac/PTTG1 axis contributed to pituitary tumor formation and may represent a potential therapeutic strategy.
Collapse
Affiliation(s)
- Jinxiang Huang
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Fenglin Zhang
- Department of Neurosurgery, Tongji Hospital, Tongji University School of Medicine, Shanghai 200065, P.R. China
| | - Guohan Hu
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Yuan Pan
- Department of Neurosurgery, No. 971 Hospital of People's Liberation Army Navy, Qingdao, Shandong 266071, P.R. China
| | - Wei Sun
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Lei Jiang
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Peng Wang
- Department of Radiology, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| | - Jiting Qiu
- Department of Neurosurgery, Ruijin Hospital North, Shanghai Jiaotong University School of Medicine, Shanghai 201803, P.R. China
| | - Xuehua Ding
- Department of Neurosurgery, Shanghai Institute of Neurosurgery, Shanghai Changzheng Hospital, Second Military Medical University, Shanghai 200003, P.R. China
| |
Collapse
|
|
7
|
Zhou L, Ng DSC, Yam JC, Chen LJ, Tham CC, Pang CP, Chu WK. Post-translational modifications on the retinoblastoma protein. J Biomed Sci 2022; 29:33. [PMID: 35650644 PMCID: PMC9161509 DOI: 10.1186/s12929-022-00818-x] [Citation(s) in RCA: 30] [Impact Index Per Article: 10.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/30/2022] [Accepted: 05/26/2022] [Indexed: 11/21/2022] Open
Abstract
The retinoblastoma protein (pRb) functions as a cell cycle regulator controlling G1 to S phase transition and plays critical roles in tumour suppression. It is frequently inactivated in various tumours. The functions of pRb are tightly regulated, where post-translational modifications (PTMs) play crucial roles, including phosphorylation, ubiquitination, SUMOylation, acetylation and methylation. Most PTMs on pRb are reversible and can be detected in non-cancerous cells, playing an important role in cell cycle regulation, cell survival and differentiation. Conversely, altered PTMs on pRb can give rise to anomalies in cell proliferation and tumourigenesis. In this review, we first summarize recent findings pertinent to how individual PTMs impinge on pRb functions. As many of these PTMs on pRb were published as individual articles, we also provide insights on the coordination, either collaborations and/or competitions, of the same or different types of PTMs on pRb. Having a better understanding of how pRb is post-translationally modulated should pave the way for developing novel and specific therapeutic strategies to treat various human diseases.
Collapse
Affiliation(s)
- Linbin Zhou
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Danny Siu-Chun Ng
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China
| | - Jason C Yam
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, China
| | - Li Jia Chen
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, China
| | - Clement C Tham
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, China
| | - Chi Pui Pang
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China
- Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, China
| | - Wai Kit Chu
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong, China.
- Hong Kong Hub of Paediatric Excellence, The Chinese University of Hong Kong, Hong Kong, China.
- Department of Ophthalmology & Visual Sciences, The Chinese University of Hong Kong, Hong Kong Eye Hospital, 147K Argyle Street, Kowloon, Hong Kong, China.
| |
Collapse
|
|
8
|
Otsuka R, Hayano K, Matsubara H. Role of sirtuins in esophageal cancer: Current status and future prospects. World J Gastrointest Oncol 2022; 14:794-807. [PMID: 35582109 PMCID: PMC9048530 DOI: 10.4251/wjgo.v14.i4.794] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 12/17/2021] [Revised: 02/02/2022] [Accepted: 03/17/2022] [Indexed: 02/06/2023] Open
Abstract
Esophageal cancer (EC) is a malignant cancer that still has a poor prognosis, although its prognosis has been improving with the development of multidisciplinary treatment modalities such as surgery, chemotherapy and radiotherapy. Therefore, identifying specific molecular markers that can be served as biomarkers for the prognosis and treatment response of EC is highly desirable to aid in the personalization and improvement of the precision of medical treatment. Sirtuins are a family of nicotinamide adenine dinucleotide (NAD+)-dependent proteins consisting of seven members (SIRT1-7). These proteins have been reported to be involved in the regulation of a variety of biological functions including apoptosis, metabolism, stress response, senescence, differentiation and cell cycle progression. Given the variety of functions of sirtuins, they are speculated to be associated in some manner with cancer progression. However, while the role of sirtuins in cancer progression has been investigated over the past few years, their precise role remains difficult to characterize, as they have both cancer-promoting and cancer-suppressing properties, depending on the type of cancer. These conflicting characteristics make research into the nature of sirtuins all the more fascinating. However, the role of sirtuins in EC remains unclear due to the limited number of reports concerning sirtuins in EC. We herein review the current findings and future prospects of sirtuins in EC.
Collapse
Affiliation(s)
- Ryota Otsuka
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
| | - Koichi Hayano
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
| | - Hisahiro Matsubara
- Department of Frontier Surgery, Graduate School of Medicine, Chiba University, Chiba 260-8670, Japan
| |
Collapse
|
|
9
|
Yang Y, Liu Y, Wang Y, Chao Y, Zhang J, Jia Y, Tie J, Hu D. Regulation of SIRT1 and Its Roles in Inflammation. Front Immunol 2022; 13:831168. [PMID: 35359990 PMCID: PMC8962665 DOI: 10.3389/fimmu.2022.831168] [Citation(s) in RCA: 244] [Impact Index Per Article: 81.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/08/2021] [Accepted: 02/15/2022] [Indexed: 12/28/2022] Open
Abstract
The silent information regulator sirtuin 1 (SIRT1) protein, a highly conserved NAD+-dependent deacetylase belonging to the sirtuin family, is a post-translational regulator that plays a role in modulating inflammation. SIRT1 affects multiple biological processes by deacetylating a variety of proteins including histones and non-histone proteins. Recent studies have revealed intimate links between SIRT1 and inflammation, while alterations to SIRT1 expression and activity have been linked to inflammatory diseases. In this review, we summarize the mechanisms that regulate SIRT1 expression, including upstream activators and suppressors that operate on the transcriptional and post-transcriptional levels. We also summarize factors that influence SIRT1 activity including the NAD+/NADH ratio, SIRT1 binding partners, and post-translational modifications. Furthermore, we underscore the role of SIRT1 in the development of inflammation by commenting on the proteins that are targeted for deacetylation by SIRT1. Finally, we highlight the potential for SIRT1-based therapeutics for inflammatory diseases.
Collapse
Affiliation(s)
- Yunshu Yang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Yang Liu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Yunwei Wang
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Yongyi Chao
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Jinxin Zhang
- Department of Emergency, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Yanhui Jia
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Jun Tie
- State Key Laboratory of Cancer Biology and Xijing Hospital of Digestive Diseases, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| | - Dahai Hu
- Department of Burns and Cutaneous Surgery, Xijing Hospital, Fourth Military Medical University, Xi’an, China
| |
Collapse
|
|
10
|
Palmer RD, Vaccarezza M. Nicotinamide adenine dinucleotide and the sirtuins caution: Pro-cancer functions. Aging Med (Milton) 2021; 4:337-344. [PMID: 34964015 PMCID: PMC8711221 DOI: 10.1002/agm2.12184] [Citation(s) in RCA: 5] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/16/2021] [Revised: 11/09/2021] [Accepted: 11/11/2021] [Indexed: 11/10/2022] Open
Abstract
This scoping review aims to perform a brief but comprehensive assessment of existing peer-reviewed literature and determine whether raising nicotinamide adenine dinucleotide can prevent or promote tumorigenesis. The examination of extensive peer-reviewed data regarding the synthesis of nicotinamide adenine dinucleotide has been performed with a focus on nuclear dynamics and the deoxyribose nucleic acid repair pathway. Various enzymatic protective functions have been identified from nicotinamide adenine dinucleotide levels, as well as the threat role that is also explored. Nicotinamide adenine dinucleotide precursors and sirtuin-activating compounds are becoming ubiquitous in the commercial market. Further research into whether elevating levels of nicotinamide adenine dinucleotide or overexpression of sirtuins can increase the potential for neoplasm or other age-related pathophysiology is warranted due to the high energy requirements of certain diseases such as cancer.
Collapse
Affiliation(s)
| | - Mauro Vaccarezza
- School of MedicineFaculty of Health SciencesCurtin UniversityBentley, PerthWestern AustraliaAustralia
| |
Collapse
|
|
11
|
Qiu P, Hou W, Wang H, Lei KKW, Wang S, Chen W, Pardeshi LA, Prothro K, Shukla Y, Su SSM, Schrump DS, Chen Q, Deng CX, Xu X, Wang R. Sirt1 deficiency upregulates glutathione metabolism to prevent hepatocellular carcinoma initiation in mice. Oncogene 2021; 40:6023-6033. [PMID: 34433910 PMCID: PMC10184507 DOI: 10.1038/s41388-021-01993-1] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/14/2020] [Revised: 05/27/2021] [Accepted: 08/10/2021] [Indexed: 02/07/2023]
Abstract
Sirtuin-1 (SIRT1) is involved in various metabolic pathways, including fatty acid synthesis and gluconeogenesis in the liver. However, its role in initiation and progression of liver cancer remains unclear. Studying Sirt1 liver-specific knockout (LKO) mice in combination with diethylnitrosamine (DEN) treatment, we demonstrated that loss of Sirt1 rendered mice resistant to DEN-induced hepatocellular carcinoma (HCC) development. RNA-seq revealed that livers from LKO mice exhibited an enrichment in glutathione metabolism eight months after DEN challenge. Sirt1 deficiency elevated the expression of glutathione-s-transferase family genes by increasing the level of Nrf2, a key regulator of glutathione metabolism. Hence, LKO livers displayed a reductive environment with an increased ratio of GSH to GSSG and an elevated GSH level. Furthermore, using CRISPR knockout techniques, we confirmed that the impairment of HCC formation in LKO mice is mainly dependent on NRF2 signaling. Meanwhile, HCC induced by DEN could be blocked by the administration of N-acetyl cysteine (NAC) when administered one month after DEN challenge. However, NAC treatment starting five months after DEN injection was not able to prevent tumor development. In conclusion, our findings indicate that a reductive environment orchestrated by glutathione metabolism at an early stage can prevent the initiation of HCC.
Collapse
Affiliation(s)
- Pengxiang Qiu
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China.,Center for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, SAR, China
| | - Weilong Hou
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China
| | - Haitao Wang
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China
| | - Kimmy Ka Wing Lei
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China
| | - Shaowei Wang
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China
| | - Weiping Chen
- National Institute of Diabetes and Digestive and Kidney Diseases, Bethesda, MD, USA
| | | | - Katherine Prothro
- Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Yashvita Shukla
- Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Samson Sek Man Su
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China.,Center for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, SAR, China
| | - David S Schrump
- Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
| | - Qiang Chen
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China.,Center for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, SAR, China
| | - Chu-Xia Deng
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China. .,Center for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, SAR, China.
| | - Xiaoling Xu
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China. .,Center for Precision Medicine Research and Training, Faculty of Health Sciences, University of Macau, Macau, SAR, China.
| | - Ruihong Wang
- Cancer Center, Faculty of Health Sciences, University of Macau, Macau, SAR, China. .,Thoracic Surgery Branch, Center for Cancer Research, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
| |
Collapse
|
|
12
|
Arras W, Vercammen H, Ní Dhubhghaill S, Koppen C, Van den Bogerd B. Proliferation Increasing Genetic Engineering in Human Corneal Endothelial Cells: A Literature Review. Front Med (Lausanne) 2021; 8:688223. [PMID: 34268324 PMCID: PMC8275833 DOI: 10.3389/fmed.2021.688223] [Citation(s) in RCA: 4] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/30/2021] [Accepted: 06/07/2021] [Indexed: 11/13/2022] Open
Abstract
The corneal endothelium is the inner layer of the cornea. Despite comprising only a monolayer of cells, dysfunction of this layer renders millions of people visually impaired worldwide. Currently, corneal endothelial transplantation is the only viable means of restoring vision for these patients. However, because the supply of corneal endothelial grafts does not meet the demand, many patients remain on waiting lists, or are not treated at all. Possible alternative treatment strategies include intracameral injection of human corneal endothelial cells (HCEnCs), biomedical engineering of endothelial grafts and increasing the HCEnC density on grafts that would otherwise have been unsuitable for transplantation. Unfortunately, the limited proliferative capacity of HCEnCs proves to be a major bottleneck to make these alternatives beneficial. To tackle this constraint, proliferation enhancing genetic engineering is being investigated. This review presents the diverse array of genes that have been targeted by different genetic engineering strategies to increase the proliferative capacity of HCEnCs and their relevance for clinical and research applications. Together these proliferation-related genes form the basis to obtain a stable and safe supply of HCEnCs that can tackle the corneal endothelial donor shortage.
Collapse
Affiliation(s)
- Wout Arras
- Antwerp Research Group for Ocular Science (ARGOS), Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Hendrik Vercammen
- Antwerp Research Group for Ocular Science (ARGOS), Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| | - Sorcha Ní Dhubhghaill
- Antwerp Research Group for Ocular Science (ARGOS), Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.,Department of Ophthalmology, Antwerp University Hospital, Edegem, Belgium.,Netherlands Institute for Innovative Ocular Surgery (NIIOS), Rotterdam, Netherlands
| | - Carina Koppen
- Antwerp Research Group for Ocular Science (ARGOS), Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium.,Department of Ophthalmology, Antwerp University Hospital, Edegem, Belgium
| | - Bert Van den Bogerd
- Antwerp Research Group for Ocular Science (ARGOS), Translational Neurosciences, Faculty of Medicine and Health Sciences, University of Antwerp, Wilrijk, Belgium
| |
Collapse
|
|
13
|
Garcia-Peterson LM, Li X. Trending topics of SIRT1 in tumorigenicity. Biochim Biophys Acta Gen Subj 2021; 1865:129952. [PMID: 34147543 DOI: 10.1016/j.bbagen.2021.129952] [Citation(s) in RCA: 42] [Impact Index Per Article: 10.5] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/26/2021] [Revised: 06/09/2021] [Accepted: 06/15/2021] [Indexed: 12/15/2022]
Abstract
BACKGROUND Carcinogenesis is governed by a series of genetic alterations and epigenetic changes that lead to aberrant patterns in neoplastic cells. Sirtuin-1(SIRT1), an NAD+-dependent protein deacetylase, is capable of deacetylating histones and non-histone substrates that regulate various physiological activities during tumorigenesis. Recent studies have identified the role of SIRT1 in different stages of cancer, including genome instability, tumor initiation, proliferation, metabolism, and therapeutic response. However, the action of SIRT1 has been reported to be both oncogenic and tumor suppressive during carcinogenesis. Consequently, the biological functions of SIRT1 in cancer remain controversial. SCOPE OF REVIEW We highlight the most recent findings on SIRT1 in different stages of tumorigenesis, and update the current status of SIRT1 small molecule modulators in clinical application of cancer treatment. MAJOR CONCLUSION By targeting both tumor suppressors and oncogenic proteins, SIRT1 has a bifunctional role at different stages of tumorigenesis. The impact of SIRT1 on tumorigenesis is also distinct at different stages and is dependent on its dosages. SIRT1 suppresses tumor initiation through its functions in promoting DNA repair, increasing genome stability, and inhibiting inflammation at the pre-cancer stage. However, SIRT1 enhances tumor proliferation, survival, and drug resistance through its roles in anti-apoptosis, pro-tumor metabolism, and anti-inflammation (inhibition of anti-tumor immunity) at the stages of tumor progression, metastasis, and relapse. Consequently, both SIRT1 inhibitors and activators have been explored for cancer treatment. GENERAL SIGNIFICANCE Better understanding the dose- and stage-dependent roles of SIRT1 in each cancer type can provide new avenues of exploration for therapy development.
Collapse
Affiliation(s)
- Liz M Garcia-Peterson
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA
| | - Xiaoling Li
- Signal Transduction Laboratory, National Institute of Environmental Health Sciences, Research Triangle Park, NC 27709, USA.
| |
Collapse
|
|
14
|
Li G, Zhong S. MicroRNA-217 inhibits the proliferation and invasion, and promotes apoptosis of non-small cell lung cancer cells by targeting sirtuin 1. Oncol Lett 2021; 21:386. [PMID: 33777209 PMCID: PMC7988702 DOI: 10.3892/ol.2021.12647] [Citation(s) in RCA: 7] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/04/2019] [Accepted: 10/22/2020] [Indexed: 11/17/2022] Open
Abstract
Non-small cell lung cancer (NSCLC) is a common malignancy worldwide. MicroRNA (miR)-217 and sirtuin 1 (SIRT1) have been reported to play significant roles in different types of cancer, such as osteosarcoma and prostate cancer; however, the association between miR-217 and SIRT1 in the cell proliferation, apoptosis and invasion of NSCLC remain unknown. Thus, the present study aimed to investigate the roles of miR-217 and SIRT1 in NSCLC. The expression levels of miR-217 and SIRT1 were detected via reverse transcription-quantitative (RT-q)PCR and western blot analyses. The effect of miR-217 on A549 and H1299 cell proliferation, apoptosis and invasion was assessed via the Cell Counting Kit-8, flow cytometry and Transwell assays, respectively. In addition, the association between SIRT1 and miR-217 was predicted using the TargetScan database, and verified via the dual-luciferase reporter assay, and RT-qPCR and western blot analyses. The results demonstrated that miR-217 expression was significantly downregulated, while SIRT1 expression was significantly upregulated in A549 and H1299 cells compared with the human bronchial epithelial cells. Furthermore, transfection with miR-217 mimic significantly inhibited A549 and H1299 cell proliferation and invasion, and induced A549 and H1299 cell apoptosis. The results of the dual-luciferase reporter assay and western blot analysis confirmed that SIRT1 is a target gene of miR-217. In addition, miR-217 inhibited the activation of AMP-activated protein kinase (AMPK) and mTOR signaling. Taken together, the results of the present study suggest that miR-217 inhibits A549 and H1299 cell proliferation and invasion, and induces A549 and H1299 cell apoptosis by targeting SIRT1 and inactivating the SIRT1-mediated AMPK/mTOR signaling pathway. Thus, miR-217 may be used as a potential therapeutic target for the treatment of patients with NSCLC.
Collapse
Affiliation(s)
- Guangshun Li
- Department of Thoracic, Xi'an Central Hospital, Xi'an, Shaanxi 710003, P.R. China
| | - Shouping Zhong
- Department of Thoracic, Xi'an Central Hospital, Xi'an, Shaanxi 710003, P.R. China
| |
Collapse
|
|
15
|
Maissan P, Mooij EJ, Barberis M. Sirtuins-Mediated System-Level Regulation of Mammalian Tissues at the Interface between Metabolism and Cell Cycle: A Systematic Review. BIOLOGY 2021; 10:194. [PMID: 33806509 PMCID: PMC7999230 DOI: 10.3390/biology10030194] [Citation(s) in RCA: 21] [Impact Index Per Article: 5.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Subscribe] [Scholar Register] [Received: 01/20/2021] [Revised: 02/20/2021] [Accepted: 02/25/2021] [Indexed: 02/06/2023]
Abstract
Sirtuins are a family of highly conserved NAD+-dependent proteins and this dependency links Sirtuins directly to metabolism. Sirtuins' activity has been shown to extend the lifespan of several organisms and mainly through the post-translational modification of their many target proteins, with deacetylation being the most common modification. The seven mammalian Sirtuins, SIRT1 through SIRT7, have been implicated in regulating physiological responses to metabolism and stress by acting as nutrient sensors, linking environmental and nutrient signals to mammalian metabolic homeostasis. Furthermore, mammalian Sirtuins have been implicated in playing major roles in mammalian pathophysiological conditions such as inflammation, obesity and cancer. Mammalian Sirtuins are expressed heterogeneously among different organs and tissues, and the same holds true for their substrates. Thus, the function of mammalian Sirtuins together with their substrates is expected to vary among tissues. Any therapy depending on Sirtuins could therefore have different local as well as systemic effects. Here, an introduction to processes relevant for the actions of Sirtuins, such as metabolism and cell cycle, will be followed by reasoning on the system-level function of Sirtuins and their substrates in different mammalian tissues. Their involvement in the healthy metabolism and metabolic disorders will be reviewed and critically discussed.
Collapse
Affiliation(s)
- Parcival Maissan
- Synthetic Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands;
| | - Eva J. Mooij
- Systems Biology, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, Surrey, UK;
- Centre for Mathematical and Computational Biology, CMCB, University of Surrey, Guildford GU2 7XH, Surrey, UK
| | - Matteo Barberis
- Synthetic Systems Biology and Nuclear Organization, Swammerdam Institute for Life Sciences, University of Amsterdam, 1098 XH Amsterdam, The Netherlands;
- Systems Biology, School of Biosciences and Medicine, Faculty of Health and Medical Sciences, University of Surrey, Guildford GU2 7XH, Surrey, UK;
- Centre for Mathematical and Computational Biology, CMCB, University of Surrey, Guildford GU2 7XH, Surrey, UK
| |
Collapse
|
|
16
|
Brockmueller A, Sameri S, Liskova A, Zhai K, Varghese E, Samuel SM, Büsselberg D, Kubatka P, Shakibaei M. Resveratrol's Anti-Cancer Effects through the Modulation of Tumor Glucose Metabolism. Cancers (Basel) 2021; 13:cancers13020188. [PMID: 33430318 PMCID: PMC7825813 DOI: 10.3390/cancers13020188] [Citation(s) in RCA: 48] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/18/2020] [Revised: 01/02/2021] [Accepted: 01/04/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary The prevention and treatment of cancer is an ongoing medical challenge. In the context of personalized medicine, the well-studied polyphenol resveratrol could complement classical tumor therapy. It may affect key processes such as inflammation, angiogenesis, proliferation, metastasis, glucose metabolism, and apoptosis in various cancers because resveratrol acts as a multi-targeting agent by modulating multiple signal transduction pathways. This review article focuses on resveratrol’s ability to modify tumor glucose metabolism and its associated therapeutic capacity. Resveratrol reduces glucose uptake and glycolysis by affecting Glut1, PFK1, HIF-1α, ROS, PDH, and the CamKKB/AMPK pathway. It also inhibits cell growth, invasion, and proliferation by targeting NF-kB, Sirt1, Sirt3, LDH, PI-3K, mTOR, PKM2, R5P, G6PD, TKT, talin, and PGAM. In addition, resveratrol induces apoptosis by targeting integrin, p53, LDH, and FAK. In conclusion, resveratrol has many potentials to intervene in tumor processes if bioavailability can be increased and this natural compound can be used selectively. Abstract Tumor cells develop several metabolic reprogramming strategies, such as increased glucose uptake and utilization via aerobic glycolysis and fermentation of glucose to lactate; these lead to a low pH environment in which the cancer cells thrive and evade apoptosis. These characteristics of tumor cells are known as the Warburg effect. Adaptive metabolic alterations in cancer cells can be attributed to mutations in key metabolic enzymes and transcription factors. The features of the Warburg phenotype may serve as promising markers for the early detection and treatment of tumors. Besides, the glycolytic process of tumors is reversible and could represent a therapeutic target. So-called mono-target therapies are often unsafe and ineffective, and have a high prevalence of recurrence. Their success is hindered by the ability of tumor cells to simultaneously develop multiple chemoresistance pathways. Therefore, agents that modify several cellular targets, such as energy restriction to target tumor cells specifically, have therapeutic potential. Resveratrol, a natural active polyphenol found in grapes and red wine and used in many traditional medicines, is known for its ability to target multiple components of signaling pathways in tumors, leading to the suppression of cell proliferation, activation of apoptosis, and regression in tumor growth. Here, we describe current knowledge on the various mechanisms by which resveratrol modulates glucose metabolism, its potential as an imitator of caloric restriction, and its therapeutic capacity in tumors.
Collapse
Affiliation(s)
- Aranka Brockmueller
- Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, Pettenkoferstrasse 11, D-80336 Munich, Germany;
| | - Saba Sameri
- Department of Molecular Medicine and Genetics, Hamadan University of Medical Sciences, 6517838678 Hamadan, Iran;
| | - Alena Liskova
- Department of Obstetrics and Gynecology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia;
| | - Kevin Zhai
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar; (K.Z.); (E.V.); (S.M.S.); (D.B.)
| | - Elizabeth Varghese
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar; (K.Z.); (E.V.); (S.M.S.); (D.B.)
| | - Samson Mathews Samuel
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar; (K.Z.); (E.V.); (S.M.S.); (D.B.)
| | - Dietrich Büsselberg
- Department of Physiology and Biophysics, Weill Cornell Medicine-Qatar, Education City, Qatar Foundation, Doha 24144, Qatar; (K.Z.); (E.V.); (S.M.S.); (D.B.)
| | - Peter Kubatka
- Department of Medical Biology, Jessenius Faculty of Medicine, Comenius University in Bratislava, 036 01 Martin, Slovakia;
| | - Mehdi Shakibaei
- Musculoskeletal Research Group and Tumor Biology, Chair of Vegetative Anatomy, Institute of Anatomy, Faculty of Medicine, Ludwig-Maximilian-University Munich, Pettenkoferstrasse 11, D-80336 Munich, Germany;
- Correspondence: ; Tel.: +49-892-1807-2624; Fax: +49-892-1807-2625
| |
Collapse
|
|
17
|
NIR promotes progression of colorectal cancer through regulating RB. BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR CELL RESEARCH 2020; 1868:118856. [PMID: 32931817 DOI: 10.1016/j.bbamcr.2020.118856] [Citation(s) in RCA: 1] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [Key Words] [Subscribe] [Scholar Register] [Received: 12/31/2019] [Revised: 08/21/2020] [Accepted: 09/09/2020] [Indexed: 01/05/2023]
Abstract
NIR, a novel INHAT, negatively regulates the transcription activity of tumor repressor p53. However, if NIR functions in the tumorigenesis dependent on the regulation of p53 remains unknown. Here, we report that NIR promotes progression of colorectal cancer (CRC) through regulating RB function. Firstly, we found that NIR expression is upregulated in the human CRC tissues and significantly associated with the poor outcome of the patients. Sequence alignment shows that NIR contains an RB-binding motif LxCxE in its INHAT-2 domain. We demonstrate that NIR interacts with RB via INHAT-2 in CRC cells and promotes RB degradation through proteasome-mediated pathway. Further, either full-length GFP-NIR or GFP-NIR-INHAT2 facilitates poly-ubiquitination of RB. In addition, NIR inhibits RB acetylation by INHAT-2, suggesting NIR might promote RB degradation through inhibiting RB acetylation. Importantly, endogenous NIR is downregulated upon DNA damage, which is consistent with the upregulation of total level and acetylation of RB. We further show that Flag-NIR inhibits DNA damage-induced RB acetylation. Thus, downregulation of NIR might contribute to maintain the cellular homeostasis under DNA damage. Consequently, depletion of NIR inhibits cell proliferation and tumor growth in mouse xenografts. Taken together, we demonstrate that NIR promotes CRC progression partially through inhibiting RB acetylation and promoting RB degradation. Targeting NIR may provide a potential therapeutic strategy for NIR-upregulated CRC patients.
Collapse
|
|
18
|
El Ters M, Zhou X, Lepping RJ, Lu P, Karcher RT, Mahnken JD, Brooks WM, Winklhofer FT, Li X, Yu AS. Biological Efficacy and Safety of Niacinamide in Patients With ADPKD. Kidney Int Rep 2020; 5:1271-1279. [PMID: 32775826 PMCID: PMC7403550 DOI: 10.1016/j.ekir.2020.06.002] [Citation(s) in RCA: 22] [Impact Index Per Article: 4.4] [Reference Citation Analysis] [Abstract] [Key Words] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/26/2020] [Revised: 05/11/2020] [Accepted: 06/02/2020] [Indexed: 12/03/2022] Open
Abstract
INTRODUCTION Autosomal dominant polycystic kidney disease (ADPKD) is characterized by progressive cyst enlargement, leading to kidney failure. Sirtuin-1 is upregulated in ADPKD and accelerates disease progression by deacetylating p53. Niacinamide is a dietary supplement that inhibits sirtuins at high doses. METHODS We conducted an open-label, single-arm intervention trial (study 1, N = 10), and a randomized, double blinded, placebo-controlled trial (study 2, N = 36) to assess the biological activity and safety of niacinamide. Patients with ADPKD were given 30 mg/kg oral niacinamide or placebo, for 12 months. The primary endpoint was the ratio of acetylated p53 to total p53 protein in peripheral blood mononuclear cells (PBMCs). RESULTS There was no sustained effect of niacinamide on acetylated/total p53 in either study and no difference between placebo and niacinamide arms. There was no difference in the change in height-adjusted total kidney volume over 12 months between niacinamide and placebo. Niacinamide was generally well tolerated. The most common adverse effects were nausea, diarrhea, gastroesophageal reflux, headache, and acneiform rash but there was no difference in their incidence between niacinamide and placebo. CONCLUSIONS In conclusion, niacinamide is safe and well-tolerated in patients with ADPKD. However, we were unable to detect a sustained inhibition of sirtuin activity over 12 months of treatment, and there was no signal to suggest a beneficial effect on any efficacy measure.
Collapse
Affiliation(s)
- Mireille El Ters
- Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, Kansas, USA
- Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Xia Zhou
- Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, Kansas, USA
- Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Rebecca J. Lepping
- Hoglund Biomedical Imaging Center, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Pengcheng Lu
- Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Rainer T. Karcher
- Hoglund Biomedical Imaging Center, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Jonathan D. Mahnken
- Department of Biostatistics and Data Science, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - William M. Brooks
- Hoglund Biomedical Imaging Center, University of Kansas Medical Center, Kansas City, Kansas, USA
- Department of Neurology, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Franz T. Winklhofer
- Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, Kansas, USA
- Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Xiaogang Li
- Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, Kansas, USA
- Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA
| | - Alan S.L. Yu
- Division of Nephrology and Hypertension, University of Kansas Medical Center, Kansas City, Kansas, USA
- Jared Grantham Kidney Institute, University of Kansas Medical Center, Kansas City, Kansas, USA
| |
Collapse
|
|
19
|
Yu L, Dong L, Li H, Liu Z, Luo Z, Duan G, Dai X, Lin Z. Ubiquitination-mediated degradation of SIRT1 by SMURF2 suppresses CRC cell proliferation and tumorigenesis. Oncogene 2020; 39:4450-4464. [PMID: 32361710 DOI: 10.1038/s41388-020-1298-0] [Citation(s) in RCA: 60] [Impact Index Per Article: 12.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/18/2019] [Revised: 04/07/2020] [Accepted: 04/09/2020] [Indexed: 02/07/2023]
Abstract
The NAD-dependent deacetylase sirtuin 1 (SIRT1), a member of the mammalian sirtuin family, plays a pivotal role in deacetylating histone and nonhistone proteins. Recently, it has been reported that SIRT1 is upregulated in various kinds of tumors and is associated with cell growth and metastasis. However, the factors and molecular mechanism regulating its cellular levels remain to be clarified. Here, we reported that the E3 ubiquitin ligase SMURF2 interacts with SIRT1 and mediates its ubiquitination and degradation. Depletion of SMURF2 leads to SIRT1 upregulation and induces the tumor formation and growth of colorectal cancer in vitro and in vivo. Furthermore, we show a negative correlation between SIRT1 and SMURF2 expression in human colorectal cancer. Thus, we propose a novel mechanism of colorectal tumorigenesis via SIRT1 regulation by SMURF2, which could potentially give rise to a new strategy for the treatment of colorectal cancer.
Collapse
Affiliation(s)
- Le Yu
- School of Life Sciences, Chongqing University, 401331, Chongqing, China
| | - Ling Dong
- School of Life Sciences, Chongqing University, 401331, Chongqing, China
| | - Hui Li
- School of Life Sciences, Chongqing University, 401331, Chongqing, China
| | - Zhaojian Liu
- Department of Cell Biology, Shandong University School of Medicine, 250012, Jinan, China
| | - Zhong Luo
- School of Life Sciences, Chongqing University, 401331, Chongqing, China
| | - Guangjie Duan
- Department of Pulmonology, Southwest Hospital, Third Military Medical University, 400038, Chongqing, China
| | - Xiaotian Dai
- Department of Pulmonology, Southwest Hospital, Third Military Medical University, 400038, Chongqing, China.
| | - Zhenghong Lin
- School of Life Sciences, Chongqing University, 401331, Chongqing, China.
| |
Collapse
|
|
20
|
Li X. Epigenetics and cell cycle regulation in cystogenesis. Cell Signal 2019; 68:109509. [PMID: 31874209 DOI: 10.1016/j.cellsig.2019.109509] [Citation(s) in RCA: 12] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/01/2019] [Revised: 12/19/2019] [Accepted: 12/20/2019] [Indexed: 12/16/2022]
Abstract
The role of genetic mutations in the development of polycystic kidney disease (PKD), such as alterations in PKD1 and PKD2 genes in autosomal dominant PKD (ADPKD), is well understood. However, the significance of epigenetic mechanisms in the progression of PKD remains unclear and is increasingly being investigated. The term of epigenetics describes a range of mechanisms in genome function that do not solely result from the DNA sequence itself. Epigenetic information can be inherited during mammalian cell division to sustain phenotype specifically and physiologically responsive gene expression in the progeny cells. A multitude of functional studies of epigenetic modifiers and systematic genome-wide mapping of epigenetic marks reveal the importance of epigenomic mechanisms, including DNA methylation, histone/chromatin modifications and non-coding RNAs, in PKD pathologies. Deregulated proliferation is a characteristic feature of cystic renal epithelial cells. Moreover, defects in many of the molecules that regulate the cell cycle have been implicated in cyst formation and progression. Recent evidence suggests that alterations of DNA methylation and histone modifications on specific genes and the whole genome involved in cell cycle regulation and contribute to the pathogenesis of PKD. This review summarizes the recent advances of epigenetic mechanisms in PKD, which helps us to define the term of "PKD epigenetics" and group PKD epigenetic changes in three categories. In particularly, this review focuses on the interplay of epigenetic mechanisms with cell cycle regulation during normal cell cycle progression and cystic cell proliferation, and discusses the potential to detect and quantify DNA methylation from body fluids as diagnostic/prognostic biomarkers. Collectively, this review provides concepts and examples of epigenetics in cell cycle regulation to reveal a broad view of different aspects of epigenetics in biology and PKD, which may facilitate to identify possible novel therapeutic intervention points and to explore epigenetic biomarkers in PKD.
Collapse
Affiliation(s)
- Xiaogang Li
- Department of Internal Medicine, Mayo Clinic, Rochester, MN 55905, United States of America; Department of Biochemistry and Molecular Biology, Mayo Clinic, Rochester, MN 55905, United States of America.
| |
Collapse
|
|
21
|
The Roles of Sirtuin Family Proteins in Cancer Progression. Cancers (Basel) 2019; 11:cancers11121949. [PMID: 31817470 PMCID: PMC6966446 DOI: 10.3390/cancers11121949] [Citation(s) in RCA: 70] [Impact Index Per Article: 11.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2019] [Revised: 11/29/2019] [Accepted: 12/02/2019] [Indexed: 12/11/2022] Open
Abstract
Sirtuin family members are characterized by either mono-ADP-ribosyltransferase or deacylase activity and are linked to various cancer-related biological pathways as regulators of transcriptional progression. Sirtuins play fundamental roles in carcinogenesis and maintenance of the malignant phenotype, mainly participating in cancer cell viability, apoptosis, metastasis, and tumorigenesis. Although sirtuin family members have a high degree of homology, they may play different roles in various kinds of cancer. This review highlights their fundamental roles in tumorigenesis and cancer development and provides a critical discussion of their dual roles in cancer, namely, as tumor promoters or tumor suppressors.
Collapse
|
|
22
|
Alves-Fernandes DK, Jasiulionis MG. The Role of SIRT1 on DNA Damage Response and Epigenetic Alterations in Cancer. Int J Mol Sci 2019; 20:E3153. [PMID: 31261609 PMCID: PMC6651129 DOI: 10.3390/ijms20133153] [Citation(s) in RCA: 235] [Impact Index Per Article: 39.2] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/30/2019] [Revised: 06/03/2019] [Accepted: 06/06/2019] [Indexed: 12/21/2022] Open
Abstract
Sirtuin-1 (SIRT1) is a class-III histone deacetylase (HDAC), an NAD+-dependent enzyme deeply involved in gene regulation, genome stability maintenance, apoptosis, autophagy, senescence, proliferation, aging, and tumorigenesis. It also has a key role in the epigenetic regulation of tissue homeostasis and many diseases by deacetylating both histone and non-histone targets. Different studies have shown ambiguous implications of SIRT1 as both a tumor suppressor and tumor promoter. However, this contradictory role seems to be determined by the cell type and SIRT1 localization. SIRT1 upregulation has already been demonstrated in some cancer cells, such as acute myeloid leukemia (AML) and primary colon, prostate, melanoma, and non-melanoma skin cancers, while SIRT1 downregulation was described in breast cancer and hepatic cell carcinomas. Even though new functions of SIRT1 have been characterized, the underlying mechanisms that define its precise role on DNA damage and repair and their contribution to cancer development remains underexplored. Here, we discuss the recent findings on the interplay among SIRT1, oxidative stress, and DNA repair machinery and its impact on normal and cancer cells.
Collapse
Affiliation(s)
| | - Miriam Galvonas Jasiulionis
- Department of Pharmacology, Escola Paulista de Medicina, Universidade Federal de São Paulo, São Paulo 04039-032, Brazil.
| |
Collapse
|
|
23
|
Vorinostat, a pan-HDAC inhibitor, abrogates productive HPV-18 DNA amplification. Proc Natl Acad Sci U S A 2018; 115:E11138-E11147. [PMID: 30385631 DOI: 10.1073/pnas.1801156115] [Citation(s) in RCA: 47] [Impact Index Per Article: 6.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 12/21/2022] Open
Abstract
Human papillomaviruses (HPVs) cause epithelial proliferative diseases. Persistent infection of the mucosal epithelia by the high-risk genotypes can progress to high-grade dysplasia and cancers. Viral transcription and protein activities are intimately linked to regulation by histone acetyltransferases and histone deacetylases (HDACs) that remodel chromatin and regulate gene expression. HDACs are also essential to remodel and repair replicating chromatin to enable the progression of replication forks. As such, Vorinostat (suberoylanilide hydroximic acid), and other pan-HDAC inhibitors, are used to treat lymphomas. Here, we investigated the effects of Vorinostat on productive infection of the high-risk HPV-18 in organotypic cultures of primary human keratinocytes. HPV DNA amplifies in the postmitotic, differentiated cells of squamous epithelia, in which the viral oncoproteins E7 and E6 establish a permissive milieu by destabilizing major tumor suppressors, the pRB family proteins and p53, respectively. We showed that Vorinostat significantly reduced these E6 and E7 activities, abrogated viral DNA amplification, and inhibited host DNA replication. The E7-induced DNA damage response, which is critical for both events, was also compromised. Consequently, Vorinostat exposure led to DNA damage and triggered apoptosis in HPV-infected, differentiated cells, whereas uninfected tissues were spared. Apoptosis was attributed to highly elevated proapoptotic Bim isoforms that are known to be repressed by EZH2 in a repressor complex containing HDACs. Two other HDAC inhibitors, Belinostat and Panobinostat, also inhibited viral DNA amplification and cause apoptosis. We suggest that HDAC inhibitors are promising therapeutic agents to treat benign HPV infections, abrogate progeny virus production, and hence interrupt transmission.
Collapse
|
|
24
|
Rifaï K, Idrissou M, Penault-Llorca F, Bignon YJ, Bernard-Gallon D. Breaking down the Contradictory Roles of Histone Deacetylase SIRT1 in Human Breast Cancer. Cancers (Basel) 2018; 10:cancers10110409. [PMID: 30380732 PMCID: PMC6266715 DOI: 10.3390/cancers10110409] [Citation(s) in RCA: 19] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/21/2018] [Revised: 10/23/2018] [Accepted: 10/26/2018] [Indexed: 02/07/2023] Open
Abstract
Breast cancer (BC) is the most common type of cancer in women worldwide; it is a multifactorial genetic disease. Acetylation and deacetylation are major post-translational protein modifications that regulate gene expression and the activity of a myriad of oncoproteins. Aberrant deacetylase activity can promote or suppress tumorigenesis and cancer metastasis in different types of human cancers, including breast cancer. Sirtuin-1 (SIRT1) is a class-III histone deacetylase (HDAC) that deacetylates both histone and non-histone targets. The often-described ‘regulator of regulators’ is deeply implicated in apoptosis, gene regulation, genome maintenance, DNA repair, aging, and cancer development. However, despite the accumulated studies over the past decade, the role of SIRT1 in human breast cancer remains a subject of debate and controversy. The ambiguity surrounding the implications of SIRT1 in breast tumorigenesis stems from the discrepancy between studies, which have shown both tumor-suppressive and promoting functions of SIRT1. Furthermore, studies have shown that SIRT1 deficiency promotes or suppresses tumors in breast cancer, making it an attractive therapeutic target in cancer treatment. This review provides a comprehensive examination of the various implications of SIRT1 in breast cancer development and metastasis. We will also discuss the mechanisms underlying the conflicting roles of SIRT1, as well as its selective modulators, in breast carcinogenesis.
Collapse
Affiliation(s)
- Khaldoun Rifaï
- Department of Oncogenetics, Centre Jean Perrin, CBRV, 28 place Henri-Dunant, 63001 Clermont-Ferrand, France.
- INSERM-UMR 1240-Imagerie Moléculaire et Stratégies Théranostiques (IMoST), 58 Rue Montalembert, 63005 Clermont-Ferrand, France.
| | - Mouhamed Idrissou
- Department of Oncogenetics, Centre Jean Perrin, CBRV, 28 place Henri-Dunant, 63001 Clermont-Ferrand, France.
- INSERM-UMR 1240-Imagerie Moléculaire et Stratégies Théranostiques (IMoST), 58 Rue Montalembert, 63005 Clermont-Ferrand, France.
| | - Frédérique Penault-Llorca
- INSERM-UMR 1240-Imagerie Moléculaire et Stratégies Théranostiques (IMoST), 58 Rue Montalembert, 63005 Clermont-Ferrand, France.
- Department of Biopathology, Centre Jean Perrin, 58 Rue Montalembert, 63011 Clermont-Ferrand, France.
| | - Yves-Jean Bignon
- Department of Oncogenetics, Centre Jean Perrin, CBRV, 28 place Henri-Dunant, 63001 Clermont-Ferrand, France.
- INSERM-UMR 1240-Imagerie Moléculaire et Stratégies Théranostiques (IMoST), 58 Rue Montalembert, 63005 Clermont-Ferrand, France.
| | - Dominique Bernard-Gallon
- Department of Oncogenetics, Centre Jean Perrin, CBRV, 28 place Henri-Dunant, 63001 Clermont-Ferrand, France.
- INSERM-UMR 1240-Imagerie Moléculaire et Stratégies Théranostiques (IMoST), 58 Rue Montalembert, 63005 Clermont-Ferrand, France.
| |
Collapse
|
|
25
|
Murofushi T, Tsuda H, Mikami Y, Yamaguchi Y, Suzuki N. CAY10591, a SIRT1 activator, suppresses cell growth, invasion, and migration in gingival epithelial carcinoma cells. J Oral Sci 2018; 59:415-423. [PMID: 28904318 DOI: 10.2334/josnusd.16-0696] [Citation(s) in RCA: 6] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 11/01/2022]
Abstract
SIRT1 is a NAD-dependent histone deacetylase that is important in a wide variety of physiological and pathophysiological processes. Although many studies have examined the relationship between SIRT1 and cancer, the role of SIRT1 in tumor malignancy is controversial. Here, we examined the effects of the SIRT1 activator CAY10591 in gingival epithelial carcinoma Ca9-22 cells. CAY10591 treatment dose- and time-dependently increased SIRT1 level and activity. The treatment decreased cell growth and induced cell-cycle repressor p21 levels. In addition, dimethyl sulfoxide significantly reduced cellular invasion and migration, and CAY10591 enhanced this decrease. Quantitative PCR analysis showed that CAY10591 decreased expression of several invasion/migration promoter genes and induced repressor genes. Our findings suggest that CAY10591 suppresses cell growth and invasion/migration activity in gingival squamous cell carcinoma Ca9-22 cells.
Collapse
Affiliation(s)
| | - Hiromasa Tsuda
- Department of Biochemistry, Nihon University School of Dentistry.,Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry
| | - Yoshikazu Mikami
- Division of Microscopic Anatomy, Niigata University Graduate School of Medical and Dental Sciences
| | - Yoko Yamaguchi
- Department of Biochemistry, Nihon University School of Dentistry.,Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry
| | - Naoto Suzuki
- Department of Biochemistry, Nihon University School of Dentistry.,Division of Functional Morphology, Dental Research Center, Nihon University School of Dentistry
| |
Collapse
|
|
26
|
Dalamaga M, Christodoulatos GS, Mantzoros CS. The role of extracellular and intracellular Nicotinamide phosphoribosyl-transferase in cancer: Diagnostic and therapeutic perspectives and challenges. Metabolism 2018; 82:72-87. [PMID: 29330025 DOI: 10.1016/j.metabol.2018.01.001] [Citation(s) in RCA: 51] [Impact Index Per Article: 7.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/16/2017] [Revised: 12/23/2017] [Accepted: 01/04/2018] [Indexed: 02/07/2023]
Abstract
Nicotinamide phosphoribosyl-transferase (Nampt) or pre-B cell colony-enhancing factor or visfatin represents a pleiotropic molecule acting as an enzyme, a cytokine and a growth factor. Intracellular Nampt plays an important role in cellular bioenergetics and metabolism, particularly NAD biosynthesis. NAD biosynthesis is critical in DNA repair, oncogenic signal transduction, transcription, genomic integrity and apoptosis. Although its insulin-mimetic function remains a controversial issue, extracellular Nampt presents proliferative, anti-apoptotic, pro-inflammatory, pro-angiogenic and metastatic properties. Nampt is upregulated in many malignancies, including obesity-associated cancers, and is associated with worse prognosis. Serum Nampt may be a potential diagnostic and prognostic biomarker in cancer. Pharmacologic agents that neutralize Nampt or medications that decrease Nampt levels or downregulate signaling pathways downstream of Nampt may prove to be useful anti-cancer treatments. In particular, Nampt inhibitors as monotherapy or in combination therapy have displayed anti-cancer activity in vivo and in vitro. The aim of this review is to explore the role of Nampt in cancer pathophysiology as well as to synopsize the mechanisms underlying the association between extracellular and intracellular Nampt, and malignancy. Exploring the interplay of cellular bioenergetics, inflammation and adiposopathy is expected to be of importance in the development of preventive and therapeutic strategies against cancer.
Collapse
Affiliation(s)
- Maria Dalamaga
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, 11527 Athens, Greece.
| | - Gerasimos Socrates Christodoulatos
- Department of Biological Chemistry, Medical School, National and Kapodistrian University of Athens, Mikras Asias 75, Goudi, 11527 Athens, Greece; Department of Microbiology, KAT Hospital, Nikis 2, Kifisia, 14561 Athens, Greece
| | - Christos S Mantzoros
- Division of Endocrinology, Diabetes and Metabolism, Beth Israel Deaconess Medical Center, Boston, MA 02215, USA; Section of Endocrinology, Boston VA Healthcare System, Harvard Medical School, Boston, MA, USA
| |
Collapse
|
|
27
|
Ong AL, Ramasamy TS. Role of Sirtuin1-p53 regulatory axis in aging, cancer and cellular reprogramming. Ageing Res Rev 2018; 43:64-80. [PMID: 29476819 DOI: 10.1016/j.arr.2018.02.004] [Citation(s) in RCA: 206] [Impact Index Per Article: 29.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/30/2017] [Revised: 01/23/2018] [Accepted: 02/16/2018] [Indexed: 12/12/2022]
Abstract
Regulatory role of Sirtuin 1 (SIRT1), one of the most extensively studied members of its kind in histone deacetylase family in governing multiple cellular fates, is predominantly linked to p53 activity. SIRT1 deacetylates p53 in a NAD+-dependent manner to inhibit transcription activity of p53, in turn modulate pathways that are implicated in regulation of tissue homoeostasis and many disease states. In this review, we discuss the role of SIRT1-p53 pathway and its regulatory axis in the cellular events which are implicated in cellular aging, cancer and reprogramming. It is noteworthy that these cellular events share few common regulatory pathways, including SIRT1-p53-LDHA-Myc, miR-34a,-Let7 regulatory network, which forms a positive feedback loop that controls cell cycle, metabolism, proliferation, differentiation, epigenetics and many others. In the context of aging, SIRT1 expression is reduced as a protective mechanism against oncogenesis and for maintenance of tissue homeostasis. Interestingly, its activation in aged cells is evidenced in response to DNA damage to protect the cells from p53-dependent apoptosis or senescence, predispose these cells to neoplastic transformation. Importantly, the dual roles of SIRT1-p53 axis in aging and tumourigenesis, either as tumour suppressor or tumour promoter are determined by SIRT1 localisation and type of cells. Conceptualising the distinct similarity between tumorigenesis and cellular reprogramming, this review provides a perspective discussion on involvement of SIRT1 in improving efficiency in the induction and maintenance of pluripotent state. Further research in understanding the role of SIRT1-p53 pathway and their associated regulators and strategies to manipulate this regulatory axis very likely foster the development of therapeutics and strategies for treating cancer and aging-associated degenerative diseases.
Collapse
|
|
28
|
Choupani J, Mansoori Derakhshan S, Bayat S, Alivand MR, Shekari Khaniani M. Narrower insight to SIRT1 role in cancer: A potential therapeutic target to control epithelial-mesenchymal transition in cancer cells. J Cell Physiol 2018; 233:4443-4457. [PMID: 29194618 DOI: 10.1002/jcp.26302] [Citation(s) in RCA: 32] [Impact Index Per Article: 4.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/22/2017] [Accepted: 11/20/2017] [Indexed: 12/12/2022]
Abstract
The epithelial-mesenchymal transition (EMT) is a highly networked cellular process which involves cell transition from the immotile epithelial to the motile mesenchymal phenotype, whereby cells lose their cell-cell adhesion and cell polarity. This important process is one of the underlying mechanisms for enabling invasion and metastasis of cancer cells which is considered as malignant phase of tumor progression. However, the molecular mechanisms of this process are not fully clarified. It is reported that Sirtuin1 (SIRT1), a NAD+ dependent class III histone deacetylase is associated with tumor metastasis through positive regulation of EMT in several types of cancers. Recent studies confirmed that up and down regulation of SIRT1 expression remarkably change the migration ability of different cancer cells in vitro and tumor metastasis in vivo. Also, according to this fact that carcinomas as the main human solid tumors, originate from different epithelial cell types, SIRT1 role in EMT has received a great attention due to its potential role in tumor development and metastasis. Therefore, SIRT1 has been proposed as a key regulator of cancer metastasis by promoting EMT, although little is known about the cleared effect of SIRT1 in this transition. Our aim in this review is to explain in more detail the role of SIRT1 in various signaling pathways related to carcinogenesis, with the focus on the promoting role of SIRT1 in EMT as a potential therapeutic target to control EMT and to prevent cancer progression.
Collapse
Affiliation(s)
- Jalal Choupani
- Immunology Research Center, Tabriz University of Medical Sciences, Tabriz, Iran.,Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sima Mansoori Derakhshan
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Sahar Bayat
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mohammad Reza Alivand
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| | - Mahmoud Shekari Khaniani
- Department of Medical Genetics, Faculty of Medicine, Tabriz University of Medical Sciences, Tabriz, Iran
| |
Collapse
|
|
29
|
Rajabi N, Galleano I, Madsen AS, Olsen CA. Targeting Sirtuins: Substrate Specificity and Inhibitor Design. PROGRESS IN MOLECULAR BIOLOGY AND TRANSLATIONAL SCIENCE 2018; 154:25-69. [PMID: 29413177 DOI: 10.1016/bs.pmbts.2017.11.003] [Citation(s) in RCA: 34] [Impact Index Per Article: 4.9] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 12/13/2022]
Abstract
Lysine residues across the proteome are modified by posttranslational modifications (PTMs) that significantly enhance the structural and functional diversity of proteins. For lysine, the most abundant PTM is ɛ-N-acetyllysine (Kac), which plays numerous roles in regulation of important cellular functions, such as gene expression (epigenetic effects) and metabolism. A family of enzymes, namely histone deacetylases (HDACs), removes these PTMs. A subset of these enzymes, the sirtuins (SIRTs), represent class III HDAC and, unlike the rest of the family, these hydrolases are NAD+-dependent. Although initially described as deacetylases, alternative deacylase functions for sirtuins have been reported, which expands the potential cellular roles of this class of enzymes. Currently, sirtuins are investigated as therapeutic targets for the treatment of diseases that span from cancers to neurodegenerative disorders. In the present book chapter, we review and discuss the current literature on novel ɛ-N-acyllysine PTMs, targeted by sirtuins, as well as mechanism-based sirtuin inhibitors inspired by their substrates.
Collapse
Affiliation(s)
- Nima Rajabi
- Center for Biopharmaceuticals, University of Copenhagen, Copenhagen, Denmark
| | - Iacopo Galleano
- Center for Biopharmaceuticals, University of Copenhagen, Copenhagen, Denmark
| | - Andreas S Madsen
- Center for Biopharmaceuticals, University of Copenhagen, Copenhagen, Denmark
| | - Christian A Olsen
- Center for Biopharmaceuticals, University of Copenhagen, Copenhagen, Denmark.
| |
Collapse
|
|
30
|
Statin and Bisphosphonate Induce Starvation in Fast-Growing Cancer Cell Lines. Int J Mol Sci 2017; 18:ijms18091982. [PMID: 28914765 PMCID: PMC5618631 DOI: 10.3390/ijms18091982] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.6] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/14/2017] [Revised: 09/04/2017] [Accepted: 09/11/2017] [Indexed: 12/11/2022] Open
Abstract
Statins and bisphosphonates are increasingly recognized as anti-cancer drugs, especially because of their cholesterol-lowering properties. However, these drugs act differently on various types of cancers. Thus, the aim of this study was to compare the effects of statins and bisphosphonates on the metabolism (NADP+/NADPH-relation) of highly proliferative tumor cell lines from different origins (PC-3 prostate carcinoma, MDA-MB-231 breast cancer, U-2 OS osteosarcoma) versus cells with a slower proliferation rate like MG-63 osteosarcoma cells. Global gene expression analysis revealed that after 6 days of treatment with pharmacologic doses of the statin simvastatin and of the bisphosphonate ibandronate, simvastatin regulated more than twice as many genes as ibandronate, including many genes associated with cell cycle progression. Upregulation of starvation-markers and a reduction of metabolism and associated NADPH production, an increase in autophagy, and a concomitant downregulation of H3K27 methylation was most significant in the fast-growing cancer cell lines. This study provides possible explanations for clinical observations indicating a higher sensitivity of rapidly proliferating tumors to statins and bisphosphonates.
Collapse
|
|
31
|
Imperatore F, Maurizio J, Vargas Aguilar S, Busch CJ, Favret J, Kowenz-Leutz E, Cathou W, Gentek R, Perrin P, Leutz A, Berruyer C, Sieweke MH. SIRT1 regulates macrophage self-renewal. EMBO J 2017; 36:2353-2372. [PMID: 28701484 DOI: 10.15252/embj.201695737] [Citation(s) in RCA: 99] [Impact Index Per Article: 12.4] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/15/2016] [Revised: 05/30/2017] [Accepted: 06/02/2017] [Indexed: 12/21/2022] Open
Abstract
Mature differentiated macrophages can self-maintain by local proliferation in tissues and can be extensively expanded in culture under specific conditions, but the mechanisms of this phenomenon remain only partially defined. Here, we show that SIRT1, an evolutionary conserved regulator of life span, positively affects macrophage self-renewal ability in vitro and in vivo Overexpression of SIRT1 during bone marrow-derived macrophage differentiation increased their proliferative capacity. Conversely, decrease of SIRT1 expression by shRNA inactivation, CRISPR/Cas9 mediated deletion and pharmacological inhibition restricted macrophage self-renewal in culture. Furthermore, pharmacological SIRT1 inhibition in vivo reduced steady state and cytokine-induced proliferation of alveolar and peritoneal macrophages. Mechanistically, SIRT1 inhibition negatively regulated G1/S transition, cell cycle progression and a network of self-renewal genes. This included inhibition of E2F1 and Myc and concomitant activation of FoxO1, SIRT1 targets mediating cell cycle progression and stress response, respectively. Our findings indicate that SIRT1 is a key regulator of macrophage self-renewal that integrates cell cycle and longevity pathways. This suggests that macrophage self-renewal might be a relevant parameter of ageing.
Collapse
Affiliation(s)
| | - Julien Maurizio
- Aix Marseille Université, CNRS, INSERM, CIML, Marseille, France
| | - Stephanie Vargas Aguilar
- Aix Marseille Université, CNRS, INSERM, CIML, Marseille, France.,Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft (MDC), Berlin, Germany
| | - Clara J Busch
- Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft (MDC), Berlin, Germany
| | - Jérémy Favret
- Aix Marseille Université, CNRS, INSERM, CIML, Marseille, France.,Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft (MDC), Berlin, Germany
| | - Elisabeth Kowenz-Leutz
- Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft (MDC), Berlin, Germany
| | - Wilfried Cathou
- Aix Marseille Université, CNRS, INSERM, CIML, Marseille, France
| | - Rebecca Gentek
- Aix Marseille Université, CNRS, INSERM, CIML, Marseille, France
| | - Pierre Perrin
- Aix Marseille Université, CNRS, INSERM, CIML, Marseille, France
| | - Achim Leutz
- Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft (MDC), Berlin, Germany
| | - Carole Berruyer
- Aix Marseille Université, CNRS, INSERM, CIML, Marseille, France
| | - Michael H Sieweke
- Aix Marseille Université, CNRS, INSERM, CIML, Marseille, France .,Max-Delbrück-Centrum für Molekulare Medizin in der Helmholtzgemeinschaft (MDC), Berlin, Germany
| |
Collapse
|
|
32
|
Reconstruction of pathway modification induced by nicotinamide using multi-omic network analyses in triple negative breast cancer. Sci Rep 2017; 7:3466. [PMID: 28615672 PMCID: PMC5471278 DOI: 10.1038/s41598-017-03322-7] [Citation(s) in RCA: 14] [Impact Index Per Article: 1.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/21/2016] [Accepted: 04/26/2017] [Indexed: 11/08/2022] Open
Abstract
Triple negative breast cancer (TNBC) is characterized by an aggressive biological behavior in the absence of a specific target agent. Nicotinamide has recently been proven to be a novel therapeutic agent for skin tumors in an ONTRAC trial. We performed combinatory transcriptomic and in-depth proteomic analyses to characterize the network of molecular interactions in TNBC cells treated with nicotinamide. The multi-omic profiles revealed that nicotinamide drives significant functional alterations related to major cellular pathways, including the cell cycle, DNA replication, apoptosis and DNA damage repair. We further elaborated the global interaction networks of molecular events via nicotinamide-inducible expression changes at the mRNA and functional protein levels. This approach indicated that nicotinamide treatment rewires interaction networks toward dysfunction in DNA damage repair and away from a pro-growth state in TNBC. To our knowledge, the high-resolution network interactions identified in the present study provide the first evidence to comprehensively support the hypothesis of nicotinamide as a novel therapeutic agent in TNBC.
Collapse
|
|
33
|
Ye Z, Fang B, Pan J, Zhang N, Huang J, Xie C, Lou T, Cao Z. miR-138 suppresses the proliferation, metastasis and autophagy of non-small cell lung cancer by targeting Sirt1. Oncol Rep 2017; 37:3244-3252. [PMID: 28498463 PMCID: PMC5442395 DOI: 10.3892/or.2017.5619] [Citation(s) in RCA: 53] [Impact Index Per Article: 6.6] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/14/2016] [Accepted: 04/11/2017] [Indexed: 01/18/2023] Open
Abstract
The present study determined the role and mechanism of miR-138 in non-small cell lung cancer (NSCLC). In total, 45 freshly resected clinical NSCLC tissues were collected. The expression of miR-138 in tissues and cell lines were determined by real-time quantitative PCR. miR-138 mimics were transfected into A549 and Calu-3 cells in vitro, and then the effects of miR-138 on lung cancer cell proliferation, cell cycle, invasion and metastasis were investigated by CCK-8 assay, Transwell and flow cytometry, respectively. The protein expression of the potential target gene Sirt1 in lung cancer cells were determined by western blot analysis. Dual-Luciferase reporter assay was performed to further confirm whether Sirt1 was the target gene of miR-138. The expression of miR-138 was significantly lower in lung cancer tissues and was negatively correlated to the differentiation degree and lymph node metastasis of lung cancer. In vitro experiment results showed that miR-138 inhibited lung cancer cell proliferation, invasion and migration. It was verified that miR-138 could downregulate Sirt1 protein expression, inhibit epithelial-mesenchymal transition (EMT), decrease the activity of AMPK signaling pathway and elevate mTOR phosphorylation level. Dual-Luciferase reporter assay demonstrated that miR-138 could directly regulate Sirt1. Downregulation of Sirt1 alone can also cause the same molecular and biological function changes. Western blot analysis and confocal microscopy results indicated that overexpression of miR-138 or interference of Sirt1 expression could inhibit lung cancer cell autophagy activity possibly through AMPK-mTOR signaling pathway. miR-138 plays a tumor suppressor function in lung cancer. It may inhibit the proliferation, invasion and migration of lung cancer through downregulation of Sirt1 expression and activation of cell autophagy. The downregulation of miR-138 is closely related to the development of lung cancer.
Collapse
Affiliation(s)
- Zaiting Ye
- The Sixth Affiliated Hospital of Wenzhou Medical University/Lishui People's Hospitlal, Lishui, Zhejiang 323000, P.R. China
| | - Bingmu Fang
- The Sixth Affiliated Hospital of Wenzhou Medical University/Lishui People's Hospitlal, Lishui, Zhejiang 323000, P.R. China
| | - Jiongwei Pan
- The Sixth Affiliated Hospital of Wenzhou Medical University/Lishui People's Hospitlal, Lishui, Zhejiang 323000, P.R. China
| | - Ning Zhang
- The Sixth Affiliated Hospital of Wenzhou Medical University/Lishui People's Hospitlal, Lishui, Zhejiang 323000, P.R. China
| | - Jinwei Huang
- The Central Hospital of Lishui City, Lishui, Zhejiang 323000, P.R. China
| | - Congying Xie
- The First Affiliated Hospital of Wenzhou Medical University, Lishui, Zhejiang 323000, P.R. China
| | - Tianzheng Lou
- The Sixth Affiliated Hospital of Wenzhou Medical University/Lishui People's Hospitlal, Lishui, Zhejiang 323000, P.R. China
| | - Zhuo Cao
- The Sixth Affiliated Hospital of Wenzhou Medical University/Lishui People's Hospitlal, Lishui, Zhejiang 323000, P.R. China
| |
Collapse
|
|
34
|
Dalamaga M, Christodoulatos GS. Visfatin, Obesity, and Cancer. ADIPOCYTOKINES, ENERGY BALANCE, AND CANCER 2017. [DOI: 10.1007/978-3-319-41677-9_6] [Citation(s) in RCA: 8] [Impact Index Per Article: 1.0] [Reference Citation Analysis] [Track Full Text] [Subscribe] [Scholar Register] [Indexed: 02/06/2023]
|
|
35
|
Sirt1 regulates glial progenitor proliferation and regeneration in white matter after neonatal brain injury. Nat Commun 2016; 7:13866. [PMID: 27991597 PMCID: PMC5187440 DOI: 10.1038/ncomms13866] [Citation(s) in RCA: 69] [Impact Index Per Article: 7.7] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/30/2016] [Accepted: 11/07/2016] [Indexed: 11/15/2022] Open
Abstract
Regenerative processes in brain pathologies require the production of distinct neural cell populations from endogenous progenitor cells. We have previously demonstrated that oligodendrocyte progenitor cell (OPC) proliferation is crucial for oligodendrocyte (OL) regeneration in a mouse model of neonatal hypoxia (HX) that reproduces diffuse white matter injury (DWMI) of premature infants. Here we identify the histone deacetylase Sirt1 as a Cdk2 regulator in OPC proliferation and response to HX. HX enhances Sirt1 and Sirt1/Cdk2 complex formation through HIF1α activation. Sirt1 deacetylates retinoblastoma (Rb) in the Rb/E2F1 complex, leading to dissociation of E2F1 and enhanced OPC proliferation. Sirt1 knockdown in culture and its targeted ablation in vivo suppresses basal and HX-induced OPC proliferation. Inhibition of Sirt1 also promotes OPC differentiation after HX. Our results indicate that Sirt1 is an essential regulator of OPC proliferation and OL regeneration after neonatal brain injury. Therefore, enhancing Sirt1 activity may promote OL recovery after DWMI.
Oligodendrocyte progenitor cell (OPC) proliferation is crucial for regeneration after hypoxic lesions in mice, a model of diffuse white matter injury of premature infants. Here, the authors show that the histone deacetylase Sirt1 is a Cdk2-dependent mediator of OPC proliferation and OPC response to hypoxia.
Collapse
|
|
36
|
Bellio MA, Rodrigues CO, Landin AM, Hatzistergos KE, Kuznetsov J, Florea V, Valasaki K, Khan A, Hare JM, Schulman IH. Physiological and hypoxic oxygen concentration differentially regulates human c-Kit+ cardiac stem cell proliferation and migration. Am J Physiol Heart Circ Physiol 2016; 311:H1509-H1519. [PMID: 27694215 PMCID: PMC5206337 DOI: 10.1152/ajpheart.00449.2016] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 06/23/2016] [Accepted: 09/24/2016] [Indexed: 02/07/2023]
Abstract
Cardiac stem cells (CSCs) are being evaluated for their efficacy in the treatment of heart failure. However, numerous factors impair the exogenously delivered cells' regenerative capabilities. Hypoxia is one stress that contributes to inadequate tissue repair. Here, we tested the hypothesis that hypoxia impairs cell proliferation, survival, and migration of human CSCs relative to physiological and room air oxygen concentrations. Human endomyocardial biopsy-derived CSCs were isolated, selected for c-Kit expression, and expanded in vitro at room air (21% O2). To assess the effect on proliferation, survival, and migration, CSCs were transferred to physiological (5%) or hypoxic (0.5%) O2 concentrations. Physiological O2 levels increased proliferation (P < 0.05) but did not affect survival of CSCs. Although similar growth rates were observed in room air and hypoxia, a significant reduction of β-galactosidase activity (-4,203 fluorescent units, P < 0.05), p16 protein expression (0.58-fold, P < 0.001), and mitochondrial content (0.18-fold, P < 0.001) in hypoxia suggests that transition from high (21%) to low (0.5%) O2 reduces senescence and promotes quiescence. Furthermore, physiological O2 levels increased migration (P < 0.05) compared with room air and hypoxia, and treatment with mesenchymal stem cell-conditioned media rescued CSC migration under hypoxia to levels comparable to physiological O2 migration (2-fold, P < 0.05 relative to CSC media control). Our finding that physiological O2 concentration is optimal for in vitro parameters of CSC biology suggests that standard room air may diminish cell regenerative potential. This study provides novel insights into the modulatory effects of O2 concentration on CSC biology and has important implications for refining stem cell therapies.
Collapse
Affiliation(s)
- Michael A Bellio
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and
| | - Claudia O Rodrigues
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and
| | - Ana Marie Landin
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and
| | | | - Jeffim Kuznetsov
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and
| | - Victoria Florea
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and
| | - Krystalenia Valasaki
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and
| | - Aisha Khan
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and
| | - Joshua M Hare
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and
| | - Ivonne Hernandez Schulman
- Interdisciplinary Stem Cell Institute, University of Miami Miller School of Medicine, Miami, Florida; and
- Division of Nephrology and Hypertension, University of Miami Miller School of Medicine, Miami, Florida
| |
Collapse
|
|
37
|
Subramaniyan B, Jagadeesan K, Ramakrishnan S, Mathan G. Targeting the interaction of Aurora kinases and SIRT1 mediated by Wnt signaling pathway in colorectal cancer: A critical review. Biomed Pharmacother 2016; 82:413-24. [DOI: 10.1016/j.biopha.2016.05.027] [Citation(s) in RCA: 8] [Impact Index Per Article: 0.9] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2015] [Revised: 05/18/2016] [Accepted: 05/18/2016] [Indexed: 12/22/2022] Open
|
|
38
|
Wang L, Zhang T, Xi Y, Yang C, Sun C, Li D. Sirtuin 1 promotes the proliferation of C2C12 myoblast cells via the myostatin signaling pathway. Mol Med Rep 2016; 14:1309-15. [PMID: 27279047 DOI: 10.3892/mmr.2016.5346] [Citation(s) in RCA: 15] [Impact Index Per Article: 1.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 05/16/2016] [Indexed: 11/05/2022] Open
Abstract
Accumulating evidence suggests that Sirtuin (Sirt)1 serves a significant role in proliferation and differentiation of myoblast cells; however the signaling mechanisms involved remain to be established. Myostatin (MSTN), a member of transforming growth factor‑β family, is an vital regulator of myoblast, fibroblast growth and differentiation. To determine if MSTN is involved in the regulation of myoblast cell proliferation by Sirt1, the present study administrated the Sirt1 activator resveratrol, inhibitor nicotinamide (NAM) and MSTN inhibitor SB431542 to C2C12 myoblast cells. It was demonstrated that the Sirt1 activator, resveratrol, repressed, whereas the Sirt1 inhibitor, NAM, enhanced C2C12 myoblast cells proliferation in a Sirt1‑dependent manner. SB431542 promoted the proliferation of C2C12 myoblast cells and reversed the inhibition effect of NAM on C2C12 myoblast cell proliferation. Additionally, resveratrol upregulated the mRNA expression of MyoD, but inhibited the expression of MSTN. Additionally, NAM significantly repressed the expression of MyoD and the phosphorylation of P107 (p‑P107), but enhanced the expression of MSTN and the protein expression of P107. SB431542 significantly mitigated the effect of NAM on the expression of MyoD, P107 and p‑P107. Taken together, these results indicated that Sirt1 promotes the proliferation of C2C12 myoblast cells via the MSTN signaling pathway.
Collapse
Affiliation(s)
- Liang Wang
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Ting Zhang
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Yongyong Xi
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Cuili Yang
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Chengcao Sun
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, Hubei 430071, P.R. China
| | - Dejia Li
- Department of Occupational and Environmental Health, School of Public Health, Wuhan University, Wuhan, Hubei 430071, P.R. China
| |
Collapse
|
|
39
|
Kohno S, Kitajima S, Sasaki N, Takahashi C. Retinoblastoma tumor suppressor functions shared by stem cell and cancer cell strategies. World J Stem Cells 2016; 8:170-84. [PMID: 27114748 PMCID: PMC4835675 DOI: 10.4252/wjsc.v8.i4.170] [Citation(s) in RCA: 12] [Impact Index Per Article: 1.3] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Received: 10/28/2015] [Revised: 12/30/2015] [Accepted: 02/14/2016] [Indexed: 02/06/2023] Open
Abstract
Carcinogenic transformation of somatic cells resembles nuclear reprogramming toward the generation of pluripotent stem cells. These events share eternal escape from cellular senescence, continuous self-renewal in limited but certain population of cells, and refractoriness to terminal differentiation while maintaining the potential to differentiate into cells of one or multiple lineages. As represented by several oncogenes those appeared to be first keys to pluripotency, carcinogenesis and nuclear reprogramming seem to share a number of core mechanisms. The retinoblastoma tumor suppressor product retinoblastoma (RB) seems to be critically involved in both events in highly complicated manners. However, disentangling such complicated interactions has enabled us to better understand how stem cell strategies are shared by cancer cells. This review covers recent findings on RB functions related to stem cells and stem cell-like behaviors of cancer cells.
Collapse
Affiliation(s)
- Susumu Kohno
- Susumu Kohno, Chiaki Takahashi, Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Shunsuke Kitajima
- Susumu Kohno, Chiaki Takahashi, Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Nobunari Sasaki
- Susumu Kohno, Chiaki Takahashi, Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| | - Chiaki Takahashi
- Susumu Kohno, Chiaki Takahashi, Division of Oncology and Molecular Biology, Cancer Research Institute, Kanazawa University, Kanazawa, Ishikawa 920-1192, Japan
| |
Collapse
|
|
40
|
Tokarz P, Kaarniranta K, Blasiak J. Role of the Cell Cycle Re-Initiation in DNA Damage Response of Post-Mitotic Cells and Its Implication in the Pathogenesis of Neurodegenerative Diseases. Rejuvenation Res 2016. [DOI: 10.1089/rej.2015.1717] [Citation(s) in RCA: 18] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Indexed: 01/25/2023] Open
Affiliation(s)
- Paulina Tokarz
- Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska, Lodz, Poland
| | - Kai Kaarniranta
- Department of Ophthalmology, Institute of Clinical Medicine, University of Eastern Finland, Kuopio, Finland
- Department of Ophthalmology, Kuopio University Hospital, Kuopio, Finland
| | - Janusz Blasiak
- Department of Molecular Genetics, Faculty of Biology and Environmental Protection, University of Lodz, Pomorska, Lodz, Poland
| |
Collapse
|
|
41
|
Zhang Y, Cai X, Chai N, Gu Y, Zhang S, Ding M, Cao H, Sha S, Yin J, Li M, Wu K, Nie Y. SIRT1 Is Reduced in Gastric Adenocarcinoma and Acts as a Potential Tumor Suppressor in Gastric Cancer. Gastrointest Tumors 2015. [DOI: 10.1159/000441460] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Submit a Manuscript] [Subscribe] [Scholar Register] [Indexed: 11/19/2022] Open
|
|
42
|
Batra A, Kashyap S, Singh L, Bakhshi S. Sirtuin1 Expression and Correlation with Histopathological Features in Retinoblastoma. Ocul Oncol Pathol 2015; 2:86-90. [PMID: 27172132 DOI: 10.1159/000439594] [Citation(s) in RCA: 5] [Impact Index Per Article: 0.5] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/09/2015] [Accepted: 08/12/2015] [Indexed: 12/29/2022] Open
Abstract
BACKGROUND Sirtuin1 (Sirt1) is a member of highly conserved proteins and has been implicated as a tumor promoter as well as a tumor suppressor. One of the mechanisms involves deacetylation of retinoblastoma protein, thereby inhibiting the tumor suppressor function. No study has been reported on the expression of Sirt1 in retinoblastoma. METHODS We assessed the expression of Sirt1 in sections of archived tissue blocks of enucleated and exenterated specimens of retinoblastoma patients by immunohistochemistry. The histopathological features were reviewed and correlated with the expression of Sirt1. The effect of Sirt1 expression on survival was also assessed. RESULTS Retrospective data of 94 patients revealed that the median age at presentation was 36 months, with a male:female ratio of 1.9:1. Fifty-one percent of the patients had International Retinoblastoma Staging System (IRSS) stage 1 disease. Of the 94 sections, 89 (95%) expressed Sirt1. Forty-eight percent of the specimens showed grade 3 staining (>75% of the cells), and the intensity was 3+ in 53%. No association between Sirt1 expression and any histopathological feature was noted. Further, Sirt1 expression did not affect the overall and progression-free survival. CONCLUSIONS Sirt1 was expressed in most of the retinoblastoma samples. However, the degree of Sirt1 expression was not associated with any high-risk histopathological feature or survival.
Collapse
Affiliation(s)
- Atul Batra
- Departments of Medical Oncology, New Delhi, India; Dr. B.R.A. Institute Rotary Cancer Hospital, New Delhi, India; All India Institute of Medical Sciences, New Delhi, India
| | - Seema Kashyap
- Departments of Ocular Pathology, New Delhi, India; All India Institute of Medical Sciences, New Delhi, India
| | - Lata Singh
- Departments of Ocular Pathology, New Delhi, India; All India Institute of Medical Sciences, New Delhi, India
| | - Sameer Bakhshi
- Departments of Medical Oncology, New Delhi, India; Dr. B.R.A. Institute Rotary Cancer Hospital, New Delhi, India; All India Institute of Medical Sciences, New Delhi, India
| |
Collapse
|
|
43
|
Haploinsufficiency for BRCA1 leads to cell-type-specific genomic instability and premature senescence. Nat Commun 2015; 6:7505. [PMID: 26106036 PMCID: PMC4491827 DOI: 10.1038/ncomms8505] [Citation(s) in RCA: 98] [Impact Index Per Article: 9.8] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 12/09/2014] [Accepted: 05/14/2015] [Indexed: 12/19/2022] Open
Abstract
Although BRCA1 function is essential for maintaining genomic integrity in all cell types, it is unclear why increased risk of cancer in individuals harbouring deleterious mutations in BRCA1 is restricted to only a select few tissues. Here we show that human mammary epithelial cells (HMECs) from BRCA1-mutation carriers (BRCA1(mut/+)) exhibit increased genomic instability and rapid telomere erosion in the absence of tumour-suppressor loss. Furthermore, we uncover a novel form of haploinsufficiency-induced senescence (HIS) specific to epithelial cells, which is triggered by pRb pathway activation rather than p53 induction. HIS and telomere erosion in HMECs correlate with misregulation of SIRT1 leading to increased levels of acetylated pRb as well as acetylated H4K16 both globally and at telomeric regions. These results identify a novel form of cellular senescence and provide a potential molecular basis for the rapid cell- and tissue- specific predisposition of breast cancer development associated with BRCA1 haploinsufficiency.
Collapse
|
|
44
|
Qiang L, Kon N, Zhao W, Jiang L, Knight CM, Welch C, Pajvani U, Gu W, Accili D. Hepatic SirT1-Dependent Gain of Function of Stearoyl-CoA Desaturase-1 Conveys Dysmetabolic and Tumor Progression Functions. Cell Rep 2015; 11:1797-1808. [PMID: 26074075 PMCID: PMC4481188 DOI: 10.1016/j.celrep.2015.05.025] [Citation(s) in RCA: 20] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/12/2015] [Revised: 04/23/2015] [Accepted: 05/12/2015] [Indexed: 12/27/2022] Open
Abstract
Obesity is associated with higher incidence of cancer, but the predisposing mechanisms remain poorly understood. The NAD(+)-dependent deacetylase SirT1 orchestrates metabolism, cellular survival, and growth. However, there is no unifying mechanism to explain the metabolic and tumor-related effects of SirT1. In this work, we demonstrate that genetic ablation of the endogenous inhibitor of SirT1, Deleted-in-Breast-Cancer-1 (Dbc1), unexpectedly results in obesity and insulin resistance. Dbc1 deficiency promoted SirT1-dependent gain of function of stearoyl-coenzyme A desaturase 1 (Scd1), increasing plasma and tissue levels of unsaturated fatty acids. The metabolic abnormalities in Dbc1(-/-) mice were reversed by ablation of hepatic SirT1 or by inhibition of Scd1 activity. Furthermore, loss of Dbc1 impaired activation of the master tumor suppressor p53 and treatment with an Scd1 inhibitor extended survival of tumor-prone TP53(-/-) mice by decreasing tumor-related death. Together, our findings illustrate a shared mechanism of obesity and tumor progression mediated by hepatic SirT1 and resulting in the activation of a key lipid synthetic enzyme, with potential therapeutic implications.
Collapse
Affiliation(s)
- Li Qiang
- Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Ning Kon
- Institute for Cancer Genetics and Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Wenhui Zhao
- Institute for Cancer Genetics and Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Le Jiang
- Institute for Cancer Genetics and Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA
| | - Colette M Knight
- Department of Medicine, Diabetes Research Center, Albert Einstein College of Medicine, Bronx, NY 10461, USA
| | - Carrie Welch
- Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Utpal Pajvani
- Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, NY 10032, USA
| | - Wei Gu
- Institute for Cancer Genetics and Department of Pathology, College of Physicians and Surgeons, Columbia University, New York, NY 10032, USA.
| | - Domenico Accili
- Naomi Berrie Diabetes Center and Department of Medicine, Columbia University, New York, NY 10032, USA.
| |
Collapse
|
|
45
|
Cheng D, Zhao L, Xu Y, Ou R, Li G, Yang H, Li W. K-Ras promotes the non-small lung cancer cells survival by cooperating with sirtuin 1 and p27 under ROS stimulation. Tumour Biol 2015; 36:7221-32. [DOI: 10.1007/s13277-015-3429-8] [Citation(s) in RCA: 11] [Impact Index Per Article: 1.1] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/04/2015] [Accepted: 04/06/2015] [Indexed: 10/23/2022] Open
|
|
46
|
Affiliation(s)
- Hui Jing
- Department
of Chemistry and
Chemical Biology, Cornell University, Ithaca, New York 14850, United States
| | - Hening Lin
- Department
of Chemistry and
Chemical Biology, Cornell University, Ithaca, New York 14850, United States
| |
Collapse
|
|
47
|
Kozako T, Suzuki T, Yoshimitsu M, Arima N, Honda SI, Soeda S. Anticancer agents targeted to sirtuins. Molecules 2014; 19:20295-313. [PMID: 25486244 PMCID: PMC6270850 DOI: 10.3390/molecules191220295] [Citation(s) in RCA: 45] [Impact Index Per Article: 4.1] [Reference Citation Analysis] [Abstract] [MESH Headings] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/04/2014] [Revised: 11/28/2014] [Accepted: 12/01/2014] [Indexed: 12/16/2022] Open
Abstract
Sirtuins are nicotinamide adenine dinucleotide+-dependent deacetylases of which there are seven isoforms (SIRT1–7). Sirtuin activity is linked to gene expression, lifespan extension, neurodegeneration, and age-related disorders. Numerous studies have suggested that sirtuins could be of great significance with regard to both antiaging and tumorigenesis, depending on its targets in specific signaling pathways or in specific cancers. Recent studies have identified small chemical compounds that modulate sirtuins, and these modulators have enabled a greater understanding of the biological function and molecular mechanisms of sirtuins. This review highlights the possibility of sirtuins, especially SIRT1 and SIRT2, for cancer therapy targets, and focuses on the therapeutic potential of sirtuin modulators both in cancer prevention and treatment.
Collapse
Affiliation(s)
- Tomohiro Kozako
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
| | - Takayoshi Suzuki
- Faculty of Medicine, Kyoto Prefectural University of Medicine, 1-5 Shimogamohangi-Cho, Sakyo-Ku, Kyoto 606-0823, Japan.
| | - Makoto Yoshimitsu
- Department of Hematology and Immunology, Kagoshima University Hospital, Kagoshima, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
| | - Naomichi Arima
- Department of Hematology and Immunology, Kagoshima University Hospital, Kagoshima, 8-35-1 Sakuragaoka, Kagoshima 890-8544, Japan.
| | - Shin-ichiro Honda
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
| | - Shinji Soeda
- Department of Biochemistry, Faculty of Pharmaceutical Sciences, Fukuoka University, 8-19-1 Nanakuma, Jonan-ku, Fukuoka 814-0180, Japan.
| |
Collapse
|
|
48
|
Clark-Knowles KV, Dewar-Darch D, Jardine KE, McBurney MW. Modulation of tumorigenesis by dietary intervention is not mediated by SIRT1 catalytic activity. PLoS One 2014; 9:e112406. [PMID: 25380034 PMCID: PMC4224430 DOI: 10.1371/journal.pone.0112406] [Citation(s) in RCA: 2] [Impact Index Per Article: 0.2] [Reference Citation Analysis] [Abstract] [MESH Headings] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 04/01/2014] [Accepted: 10/14/2014] [Indexed: 12/31/2022] Open
Abstract
The protein deacetylase SIRT1 is involved in the regulation of a large number of cellular processes that are thought to be required for cancer initiation and progression. Both SIRT1 activity and tumorigenesis can be influenced by dietary fat and polyphenolics. We set out to determine whether dietary modulations of tumorigenesis are mediated by SIRT1 catalytic functions. We introduced a mammary gland tumor-inducing transgene, MMTV-PyMT, into stocks of mice bearing a H355Y point mutation in the Sirt1 gene that abolishes SIRT1 catalytic activity. Tumor latency was reduced in animals fed a high fat diet but this effect was not dependent on SIRT1 activity. Resveratrol had little effect on tumor formation except in animals heterozygous for the mutant Sirt1 gene. We conclude that the effects of these dietary interventions on tumorigenesis are not mediated by modulation of SIRT1 catalytic activity.
Collapse
MESH Headings
- Analysis of Variance
- Animals
- Antigens, Polyomavirus Transforming/genetics
- Antineoplastic Agents, Phytogenic/pharmacology
- Biocatalysis
- Cell Transformation, Neoplastic/drug effects
- Cell Transformation, Neoplastic/genetics
- Diet, High-Fat
- Heterozygote
- Male
- Mammary Neoplasms, Experimental/diet therapy
- Mammary Neoplasms, Experimental/genetics
- Mammary Neoplasms, Experimental/metabolism
- Mammary Tumor Virus, Mouse/genetics
- Mice, Transgenic
- Point Mutation
- Resveratrol
- Sirtuin 1/genetics
- Sirtuin 1/metabolism
- Stilbenes/pharmacology
- Tumor Burden/drug effects
- Tumor Burden/genetics
Collapse
Affiliation(s)
| | - Danielle Dewar-Darch
- Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Karen E. Jardine
- Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
| | - Michael W. McBurney
- Centre for Cancer Therapeutics, Ottawa Hospital Research Institute, Ottawa, Ontario, Canada
- Department of Medicine, University of Ottawa, Ottawa, Ontario, Canada
| |
Collapse
|
|
49
|
Mir-34a mimics are potential therapeutic agents for p53-mutated and chemo-resistant brain tumour cells. PLoS One 2014; 9:e108514. [PMID: 25250818 PMCID: PMC4177398 DOI: 10.1371/journal.pone.0108514] [Citation(s) in RCA: 30] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/15/2014] [Accepted: 08/25/2014] [Indexed: 01/26/2023] Open
Abstract
Chemotherapeutic drug resistance and relapse remains a major challenge for paediatric (medulloblastoma) and adult (glioblastoma) brain tumour treatment. Medulloblastoma tumours and cell lines with mutations in the p53 signalling pathway have been shown to be specifically insensitive to DNA damaging agents. The aim of this study was to investigate the potential of triggering cell death in p53 mutated medulloblastoma cells by a direct activation of pro-death signalling downstream of p53 activation. Since non-coding microRNAs (miRNAs) have the ability to fine tune the expression of a variety of target genes, orchestrating multiple downstream effects, we hypothesised that triggering the expression of a p53 target miRNA could induce cell death in chemo-resistant cells. Treatment with etoposide, increased miR-34a levels in a p53-dependent fashion and the level of miR-34a transcription was correlated with the cell sensitivity to etoposide. miR-34a activity was validated by measuring the expression levels of one of its well described target: the NADH dependent sirtuin1 (SIRT1). Whilst drugs directly targeting SIRT1, were potent to trigger cell death at high concentrations only, introduction of synthetic miR-34a mimics was able to induce cell death in p53 mutated medulloblastoma and glioblastoma cell lines. Our results show that the need of a functional p53 signaling pathway can be bypassed by direct activation of miR-34a in brain tumour cells.
Collapse
|
|
50
|
Guan D, Lim JH, Peng L, Liu Y, Lam M, Seto E, Kao HY. Deacetylation of the tumor suppressor protein PML regulates hydrogen peroxide-induced cell death. Cell Death Dis 2014; 5:e1340. [PMID: 25032863 PMCID: PMC4123062 DOI: 10.1038/cddis.2014.185] [Citation(s) in RCA: 33] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 01/14/2014] [Revised: 03/18/2014] [Accepted: 03/26/2014] [Indexed: 12/29/2022]
Abstract
The promyelocytic leukemia protein (PML) is a tumor suppressor that is expressed at a low level in various cancers. Although post-translational modifications including SUMOylation, phosphorylation, and ubiquitination have been found to regulate the stability or activity of PML, little is known about the role of its acetylation in the control of cell survival. Here we demonstrate that acetylation of lysine 487 (K487) and SUMO1 conjugation of K490 at PML protein are mutually exclusive. We found that hydrogen peroxide (H2O2) promotes PML deacetylation and identified SIRT1 and SIRT5 as PML deacetylases. Both SIRT1 and SIRT5 are required for H2O2-mediated deacetylation of PML and accumulation of nuclear PML protein in HeLa cells. Knockdown of SIRT1 reduces the number of H2O2-induced PML-nuclear bodies (NBs) and increases the survival of HeLa cells. Ectopic expression of wild-type PML but not the K487R mutant rescues H2O2-induced cell death in SIRT1 knockdown cells. Furthermore, ectopic expression of wild-type SIRT5 but not a catalytic defective mutant can also restore H2O2-induced cell death in SIRT1 knockdown cells. Taken together, our findings reveal a novel regulatory mechanism in which SIRT1/SIRT5-mediated PML deacetylation plays a role in the regulation of cancer cell survival.
Collapse
Affiliation(s)
- D Guan
- Department of Biochemistry, School of Medicine, Case Western Reserve University, and Comprehensive Cancer Center of Case Western Reserve University, Cleveland, OH, USA
| | - J H Lim
- Department of Biochemistry, School of Medicine, Case Western Reserve University, and Comprehensive Cancer Center of Case Western Reserve University, Cleveland, OH, USA
| | - L Peng
- H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - Y Liu
- Department of Biochemistry, School of Medicine, Case Western Reserve University, and Comprehensive Cancer Center of Case Western Reserve University, Cleveland, OH, USA
| | - M Lam
- Department of Dermatology, University Hospitals Case Medical Center, Case Western Reserve University, Cleveland, OH, USA
| | - E Seto
- H Lee Moffitt Cancer Center and Research Institute, Tampa, FL, USA
| | - H-Y Kao
- Department of Biochemistry, School of Medicine, Case Western Reserve University, and Comprehensive Cancer Center of Case Western Reserve University, Cleveland, OH, USA
| |
Collapse
|