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Weidle UH, Nopora A. CircRNAs in Pancreatic Cancer: New Tools for Target Identification and Therapeutic Intervention. Cancer Genomics Proteomics 2024; 21:327-349. [PMID: 38944427 PMCID: PMC11215428 DOI: 10.21873/cgp.20451] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 05/07/2024] [Revised: 06/03/2024] [Accepted: 06/04/2024] [Indexed: 07/01/2024] Open
Abstract
We have reviewed the literature for circular RNAs (circRNAs) with efficacy in preclinical pancreatic-cancer related in vivo models. The identified circRNAs target chemoresistance mechanisms (n=5), secreted proteins and transmembrane receptors (n=15), transcription factors (n=9), components of the signaling- (n=11), ubiquitination- (n=2), autophagy-system (n=2), and others (n=9). In addition to identifying targets for therapeutic intervention, circRNAs are potential new entities for treatment of pancreatic cancer. Up-regulated circRNAs can be inhibited by antisense oligonucleotides (ASO), small interfering RNAs (siRNAs), short hairpin RNAs (shRNAs) or clustered regularly interspaced short-palindromic repeats-CRISPR associated protein (CRISPR-CAS)-based intervention. The function of down-regulated circRNAs can be reconstituted by replacement therapy using plasmids or virus-based vector systems. Target validation experiments and the development of improved delivery systems for corresponding agents were examined.
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Affiliation(s)
- Ulrich H Weidle
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
| | - Adam Nopora
- Roche Pharma Research and Early Development, Roche Innovation Center Munich, Penzberg, Germany
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2
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Jama M, Zhang M, Poile C, Nakas A, Sharkey A, Dzialo J, Dawson A, Kutywayo K, Fennell DA, Hollox EJ. Gene fusions during the early evolution of mesothelioma correlate with impaired DNA repair and Hippo pathways. Genes Chromosomes Cancer 2024; 63:e23189. [PMID: 37421230 DOI: 10.1002/gcc.23189] [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: 05/03/2023] [Revised: 06/23/2023] [Accepted: 06/27/2023] [Indexed: 07/10/2023] Open
Abstract
Malignant pleural mesothelioma (MPM), a rare cancer a long latency period (up to 40 years) between asbestos exposure and disease presentation. The mechanisms coupling asbestos to recurrent somatic alterations are poorly defined. Gene fusions arising through genomic instability may create novel drivers during early MPM evolution. We explored the gene fusions that occurred early in the evolutionary history of the tumor. We conducted multiregional whole exome sequencing (WES) of 106 samples from 20 patients undergoing pleurectomy decortication and identified 24 clonal nonrecurrent gene fusions, three of which were novel (FMO9P-OR2W5, GBA3, and SP9). The number of early gene fusion events detected varied from zero to eight per tumor, and presence of gene fusions was associated with clonal losses involving the Hippo pathway genes and homologous recombination DNA repair genes. Fusions involved known tumor suppressors BAP1, MTAP, and LRP1B, and a clonal oncogenic fusion involving CACNA1D-ERC2, PARD3B-NT5DC2, and STAB2-NT5DC2 fusions were also identified as clonal fusions. Gene fusions events occur early during MPM evolution. Individual fusions are rare as no recurrent truncal fusions event were found. This suggests the importance of early disruption of these pathways in generating genomic rearrangements resulting in potentially oncogenic gene fusions.
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Affiliation(s)
- Maymun Jama
- Department of Genetics and Genome Biology, University of Leicester, Leicester, UK
| | - Min Zhang
- Mesothelioma Research Programme, Leicester Cancer Research Centre, University of Leicester, Leicester, UK
- Novogene Corpotation Ltd., Building 301, Beijing, China
| | - Charlotte Poile
- Mesothelioma Research Programme, Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Apostolos Nakas
- Thoracic Medical Oncology, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Annabel Sharkey
- Department of Cardio-Thoracic Surgery, Sheffield Teaching Hospital NHS Trust, Sheffield, UK
| | - Joanna Dzialo
- Mesothelioma Research Programme, Leicester Cancer Research Centre, University of Leicester, Leicester, UK
| | - Alan Dawson
- Thoracic Medical Oncology, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Kudazyi Kutywayo
- Mesothelioma Research Programme, Leicester Cancer Research Centre, University of Leicester, Leicester, UK
- Department of Cardio-Thoracic Surgery, Sheffield Teaching Hospital NHS Trust, Sheffield, UK
| | - Dean A Fennell
- Department of Genetics and Genome Biology, University of Leicester, Leicester, UK
- Mesothelioma Research Programme, Leicester Cancer Research Centre, University of Leicester, Leicester, UK
- Thoracic Medical Oncology, University Hospitals of Leicester NHS Trust, Leicester, UK
| | - Edward J Hollox
- Department of Genetics and Genome Biology, University of Leicester, Leicester, UK
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3
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Li C, Cai J, Liu W, Gao Z, Li G. Downregulation of circ-STK39 suppresses pancreatic cancer progression by sponging mir-140-3p and regulating TRAM2-mediated epithelial-mesenchymal transition. Apoptosis 2023; 28:1024-1034. [PMID: 37041422 DOI: 10.1007/s10495-023-01813-9] [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] [Accepted: 01/05/2023] [Indexed: 04/13/2023]
Abstract
BACKGROUND Pancreatic cancer (PC) is amongst the most lethal gastrointestinal tumors, which is the seventh leading reason of cancer-related mortality worldwide. Previous studies have indicated that circular RNAs (circRNAs), which is a new type of endogenous noncoding RNA (ncRNA), can mediate tumor progression in diverse tumor types including PC. Whereas precise roles regarding circRNAs and their underlying regulatory mechanisms in PC remain unknown. METHODS In the current study, we employed next generation sequencing (NGS) to characterize abnormally expressed circRNAs among PC tissues. Next, we assessed expression levels of one identified circRNA, circ-STK39, in PC cell lines and tissues. Then, using bioinformatics analysis, luciferase reporter, Transwell migration, EdU and CCK-8 assays, we examined the regulatory mechanisms and targets of circ-STK39. Finally, our group explored the circ-STK39 role in PC tumor growth and metastasis in vivo. RESULTS Our team discovered that circ-STK39 expression increased in PC tissues and cells, suggesting that circ-STK39 may have a role in PC progression. Downregulation of circ-STK39 inhibited PC proliferation and migration. Bioinformatics and luciferase reporter outcomes demonstrated that TRAM2 and miR-140-3p were circ-STK39 downstream targets. TRAM2 overexpression reversed the miR-140-3p overexpression effects upon migration, proliferation and the epithelial-mesenchymal transition (EMT). CONCLUSION In this regard, we showed that circ-STK39 downregulation led to decreased migration, proliferation and the EMT of PC via the miR-140-3p/TRAM2 axis.
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Affiliation(s)
- Chao Li
- Department of Hepatobiliary Surgery, Second Affiliated Hospital Zhejiang University School of Medicine, Jiefang Road No. 88, Hangzhou, Zhejiang Province, 310009, China
| | - Juanjuan Cai
- Department of Pathology, Zhejiang Provincial People's Hospital, Hangzhou, Zhejiang Province, China
| | - Weifeng Liu
- Department of Hepatobiliary Surgery, Second Affiliated Hospital Zhejiang University School of Medicine, Jiefang Road No. 88, Hangzhou, Zhejiang Province, 310009, China
| | - Zhenzhen Gao
- Department of Hepatobiliary Surgery, Second Affiliated Hospital Zhejiang University School of Medicine, Jiefang Road No. 88, Hangzhou, Zhejiang Province, 310009, China
| | - Guogang Li
- Department of Hepatobiliary Surgery, Second Affiliated Hospital Zhejiang University School of Medicine, Jiefang Road No. 88, Hangzhou, Zhejiang Province, 310009, China.
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Barbosa IAM, Gopalakrishnan R, Mercan S, Mourikis TP, Martin T, Wengert S, Sheng C, Ji F, Lopes R, Knehr J, Altorfer M, Lindeman A, Russ C, Naumann U, Golji J, Sprouffske K, Barys L, Tordella L, Schübeler D, Schmelzle T, Galli GG. Cancer lineage-specific regulation of YAP responsive elements revealed through large-scale functional epigenomic screens. Nat Commun 2023; 14:3907. [PMID: 37400441 DOI: 10.1038/s41467-023-39527-w] [Citation(s) in RCA: 9] [Impact Index Per Article: 4.5] [Reference Citation Analysis] [Abstract] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 08/18/2022] [Accepted: 06/14/2023] [Indexed: 07/05/2023] Open
Abstract
YAP is a key transcriptional co-activator of TEADs, it regulates cell growth and is frequently activated in cancer. In Malignant Pleural Mesothelioma (MPM), YAP is activated by loss-of-function mutations in upstream components of the Hippo pathway, while, in Uveal Melanoma (UM), YAP is activated in a Hippo-independent manner. To date, it is unclear if and how the different oncogenic lesions activating YAP impact its oncogenic program, which is particularly relevant for designing selective anti-cancer therapies. Here we show that, despite YAP being essential in both MPM and UM, its interaction with TEAD is unexpectedly dispensable in UM, limiting the applicability of TEAD inhibitors in this cancer type. Systematic functional interrogation of YAP regulatory elements in both cancer types reveals convergent regulation of broad oncogenic drivers in both MPM and UM, but also strikingly selective programs. Our work reveals unanticipated lineage-specific features of the YAP regulatory network that provide important insights to guide the design of tailored therapeutic strategies to inhibit YAP signaling across different cancer types.
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Affiliation(s)
- Inês A M Barbosa
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Rajaraman Gopalakrishnan
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
- Alltrna Inc., One Kendall Square, Cambridge, MA, USA
| | - Samuele Mercan
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Thanos P Mourikis
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Typhaine Martin
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Simon Wengert
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
- Helmholtz Pioneer Campus, Helmholtz Zentrum München GmbH German Research Center for Environmental Health, Neuherberg, Germany
| | - Caibin Sheng
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Fei Ji
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Rui Lopes
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
- Roche Pharmaceutical Research and Early Development, Basel, Switzerland
| | - Judith Knehr
- Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Marc Altorfer
- Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Alicia Lindeman
- Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Carsten Russ
- Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Ulrike Naumann
- Chemical Biology and Therapeutics, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Javad Golji
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Cambridge, MA, USA
| | - Kathleen Sprouffske
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Louise Barys
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Luca Tordella
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Dirk Schübeler
- Friedrich Miescher Institute for Biomedical Research, Basel, Switzerland
- Faculty of Sciences, University of Basel, Basel, Switzerland
| | - Tobias Schmelzle
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland
| | - Giorgio G Galli
- Disease Area Oncology, Novartis Institutes for Biomedical Research, Basel, Switzerland.
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Xu F, Yan J, Peng Z, Liu J, Li Z. Comprehensive analysis of a glycolysis and cholesterol synthesis-related genes signature for predicting prognosis and immune landscape in osteosarcoma. Front Immunol 2022; 13:1096009. [PMID: 36618348 PMCID: PMC9822727 DOI: 10.3389/fimmu.2022.1096009] [Citation(s) in RCA: 12] [Impact Index Per Article: 4.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 11/11/2022] [Accepted: 12/09/2022] [Indexed: 12/24/2022] Open
Abstract
Background Glycolysis and cholesterol synthesis are crucial in cancer metabolic reprogramming. The aim of this study was to identify a glycolysis and cholesterol synthesis-related genes (GCSRGs) signature for effective prognostic assessments of osteosarcoma patients. Methods Gene expression data and clinical information were obtained from GSE21257 and TARGET-OS datasets. Consistent clustering method was used to identify the GCSRGs-related subtypes. Univariate Cox regression and LASSO Cox regression analyses were used to construct the GCSRGs signature. The ssGSEA method was used to analyze the differences in immune cells infiltration. The pRRophetic R package was utilized to assess the drug sensitivity of different groups. Western blotting, cell viability assay, scratch assay and Transwell assay were used to perform cytological validation. Results Through bioinformatics analysis, patients diagnosed with osteosarcoma were classified into one of 4 subtypes (quiescent, glycolysis, cholesterol, and mixed subtypes), which differed significantly in terms of prognosis and tumor microenvironment. Weighted gene co-expression network analysis revealed that the modules strongly correlated with glycolysis and cholesterol synthesis were the midnight blue and the yellow modules, respectively. Both univariate and LASSO Cox regression analyses were conducted on screened module genes to identify 5 GCSRGs (RPS28, MCAM, EN1, TRAM2, and VEGFA) constituting a prognostic signature for osteosarcoma patients. The signature was an effective prognostic predictor, independent of clinical characteristics, as verified further via Kaplan-Meier analysis, ROC curve analysis, univariate and multivariate Cox regression analysis. Additionally, GCSRGs signature had strong correlation with drug sensitivity, immune checkpoints and immune cells infiltration. In cytological experiments, we selected TRAM2 as a representative gene to validate the validity of GCSRGs signature, which found that TRAM2 promoted the progression of osteosarcoma cells. Finally, at the pan-cancer level, TRAM2 had been correlated with overall survival, progression free survival, disease specific survival, tumor mutational burden, microsatellite instability, immune checkpoints and immune cells infiltration. Conclusion Therefore, we constructed a GCSRGs signature that efficiently predicted osteosarcoma patient prognosis and guided therapy.
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Affiliation(s)
- Fangxing Xu
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Jinglong Yan
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China,*Correspondence: Jinglong Yan,
| | - Zhibin Peng
- Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Jingsong Liu
- Department of Orthopedics, The First Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
| | - Zecheng Li
- Department of Orthopedics, The Second Affiliated Hospital of Harbin Medical University, Harbin, Heilongjiang, China
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Suppression of heparan sulfation re-sensitizes YAP1-driven melanoma to MAPK pathway inhibitors. Oncogene 2022; 41:3953-3968. [PMID: 35798875 PMCID: PMC9355870 DOI: 10.1038/s41388-022-02400-z] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2022] [Revised: 06/20/2022] [Accepted: 06/24/2022] [Indexed: 11/08/2022]
Abstract
Accumulating evidence identifies non-genetic mechanisms substantially contributing to drug resistance in cancer patients. Preclinical and clinical data implicate the transcriptional co-activators YAP1 and its paralog TAZ in resistance to multiple targeted therapies, highlighting the strong need for therapeutic strategies overcoming YAP1/TAZ-mediated resistance across tumor entities. Here, we show particularly high YAP1/TAZ activity in MITFlow/AXLhigh melanomas characterized by resistance to MAPK pathway inhibition and broad receptor tyrosine kinase activity. To uncover genetic dependencies of melanoma cells with high YAP1/TAZ activity, we used a genome-wide CRISPR/Cas9 functional screen and identified SLC35B2, the 3′-phosphoadenosine-5′-phosphosulfate transporter of the Golgi apparatus, as an essential gene for YAP1/TAZ-driven drug resistance. SLC35B2 expression correlates with tumor progression, and its loss decreases heparan sulfate expression, reduces receptor tyrosine kinase activity, and sensitizes resistant melanoma cells to BRAF inhibition in vitro and in vivo. Thus, targeting heparan sulfation via SLC35B2 represents a novel approach for breaking receptor tyrosine kinase-mediated resistance to MAPK pathway inhibitors.
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7
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Wang K, Mei S, Cai M, Zhai D, Zhang D, Yu J, Ni Z, Yu C. Ferroptosis-Related Long Noncoding RNAs as Prognostic Biomarkers for Ovarian Cancer. Front Oncol 2022; 12:888699. [PMID: 35756659 PMCID: PMC9218568 DOI: 10.3389/fonc.2022.888699] [Citation(s) in RCA: 9] [Impact Index Per Article: 3.0] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/03/2022] [Accepted: 04/27/2022] [Indexed: 12/11/2022] Open
Abstract
Ovarian cancer (OC) is a highly malignant gynecologic tumor with few treatments available and poor prognosis with the currently available diagnostic markers and interventions. More effective methods for diagnosis and treatment are urgently needed. Although the current evidence implicates ferroptosis in the development and therapeutic responses of various types of tumors, it is unclear to what extent ferroptosis affects OC. To explore the potential of ferroptosis-related genes as biomarkers and molecular targets for OC diagnosis and intervention, this study collected several datasets from The Cancer Genome Atlas-OC (TCGA-OC), analyzed and identified the coexpression profiles of 60 ferroptosis-related genes and two subtypes of OC with respect to ferroptosis and further examined and analyzed the differentially expressed genes between the two subtypes. The results indicated that the expression levels of ferroptosis genes were significantly correlated with prognosis in patients with OC. Single-factor Cox and LASSO analysis identified eight lncRNAs from the screened ferroptosis-related genes, including lncRNAs RP11-443B7.3, RP5-1028K7.2, TRAM2-AS1, AC073283.4, RP11-486G15.2, RP11-95H3.1, RP11-958F21.1, and AC006129.1. A risk scoring model was constructed from the ferroptosis-related lncRNAs and showed good performance in the evaluation of OC patient prognosis. The high- and low-risk groups based on tumor scores presented obvious differences in clinical characteristics, tumor mutation burden, and tumor immune cell infiltration, indicating that the risk score has a good ability to predict the benefit of immunotherapy and may provide data to support the implementation of precise immunotherapy for OC. Although in vivo tests and research are needed in the future, our bioinformatics analysis powerfully supported the effectiveness of the risk signature of ferroptosis-related lncRNAs for prognosis prediction in OC. The findings suggest that these eight identified lncRNAs have great potential for development as diagnostic markers and intervention targets for OC and that patients with high ferroptosis-related lncRNA expression will receive greater benefits from conventional chemotherapy or treatment with ferroptosis inducers.
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Affiliation(s)
- Kaili Wang
- Department of Traditional Chinese Gynecology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Shanshan Mei
- Department of Traditional Chinese Gynecology, The First Affiliated Hospital of Naval Medical University, Shanghai, China.,Department of Gynecology of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
| | - Mengcheng Cai
- Department of Traditional Chinese Gynecology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Dongxia Zhai
- Department of Traditional Chinese Gynecology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Danying Zhang
- Department of Traditional Chinese Gynecology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Jin Yu
- Department of Traditional Chinese Gynecology, The First Affiliated Hospital of Naval Medical University, Shanghai, China.,International Peace Maternity and Child Health Hospital, School of Medicine, Shanghai Jiao Tong University, Shanghai, China
| | - Zhexin Ni
- Department of Traditional Chinese Gynecology, The First Affiliated Hospital of Naval Medical University, Shanghai, China
| | - Chaoqin Yu
- Department of Traditional Chinese Gynecology, The First Affiliated Hospital of Naval Medical University, Shanghai, China.,Department of Gynecology of Traditional Chinese Medicine, Shanghai University of Traditional Chinese Medicine, Shanghai, China
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8
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Hsu SC, Lin CY, Lin YY, Collins CC, Chen CL, Kung HJ. TEAD4 as an Oncogene and a Mitochondrial Modulator. Front Cell Dev Biol 2022; 10:890419. [PMID: 35602596 PMCID: PMC9117765 DOI: 10.3389/fcell.2022.890419] [Citation(s) in RCA: 8] [Impact Index Per Article: 2.7] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/05/2022] [Accepted: 04/18/2022] [Indexed: 11/13/2022] Open
Abstract
TEAD4 (TEA Domain Transcription Factor 4) is well recognized as the DNA-anchor protein of YAP transcription complex, which is modulated by Hippo, a highly conserved pathway in Metazoa that controls organ size through regulating cell proliferation and apoptosis. To acquire full transcriptional activity, TEAD4 requires co-activator, YAP (Yes-associated protein) or its homolog TAZ (transcriptional coactivator with PDZ-binding motif) the signaling hub that relays the extracellular stimuli to the transcription of target genes. Growing evidence suggests that TEAD4 also exerts its function in a YAP-independent manner through other signal pathways. Although TEAD4 plays an essential role in determining that differentiation fate of the blastocyst, it also promotes tumorigenesis by enhancing metastasis, cancer stemness, and drug resistance. Upregulation of TEAD4 has been reported in several cancers, including colon cancer, gastric cancer, breast cancer, and prostate cancer and serves as a valuable prognostic marker. Recent studies show that TEAD4, but not other members of the TEAD family, engages in regulating mitochondrial dynamics and cell metabolism by modulating the expression of mitochondrial- and nuclear-encoded electron transport chain genes. TEAD4’s functions including oncogenic activities are tightly controlled by its subcellular localization. As a predominantly nuclear protein, its cytoplasmic translocation is triggered by several signals, such as osmotic stress, cell confluency, and arginine availability. Intriguingly, TEAD4 is also localized in mitochondria, although the translocation mechanism remains unclear. In this report, we describe the current understanding of TEAD4 as an oncogene, epigenetic regulator and mitochondrial modulator. The contributing mechanisms will be discussed.
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Affiliation(s)
- Sheng-Chieh Hsu
- Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Ching-Yu Lin
- Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
| | - Yen-Yi Lin
- Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Colin C. Collins
- Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
| | - Chia-Lin Chen
- Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Vancouver Prostate Centre and Department of Urologic Sciences, University of British Columbia, Vancouver, BC, Canada
- *Correspondence: Chia-Lin Chen, ; Hsing-Jien Kung,
| | - Hsing-Jien Kung
- Program for Cancer Biology and Drug Discovery, College of Medical Science and Technology, Taipei Medical University, Taipei, Taiwan
- Research Center of Cancer Translational Medicine, Taipei Medical University, Taipei, Taiwan
- Institute of Molecular and Genomic Medicine, National Health Research Institutes, Zhunan, Taiwan
- Department of Biochemistry and Molecular Medicine, Comprehensive Cancer Center, University of California, Davis, Sacramento, CA, United States
- *Correspondence: Chia-Lin Chen, ; Hsing-Jien Kung,
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Tan C, Xia P, Zhang H, Xu K, Liu P, Guo D, Liu Z. YY1-Targeted RBM15B Promotes Hepatocellular Carcinoma Cell Proliferation and Sorafenib Resistance by Promoting TRAM2 Expression in an m6A-Dependent Manner. Front Oncol 2022; 12:873020. [PMID: 35494016 PMCID: PMC9046568 DOI: 10.3389/fonc.2022.873020] [Citation(s) in RCA: 6] [Impact Index Per Article: 2.0] [Reference Citation Analysis] [Abstract] [Grants] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 02/10/2022] [Accepted: 03/22/2022] [Indexed: 12/11/2022] Open
Abstract
As one of the most common internal modifications in eukaryotic mRNA, N6-methyladenosine (m6A) modification is involved in the pathogenesis of many diseases, including hepatocellular carcinoma (HCC). In this study, we explored the prognostic significance of the expression of RNA binding motif protein 15B (RBM15B) in HCC, by studying specimens collected from clinical subjects. RBM15B is highly expressed in HCC patients and indicates a poor prognosis. Functionally, overexpression of RBM15B promotes HCC cell proliferation and invasion and induces sorafenib resistance in HCC cells. Mechanistically, we confirmed that RBM15B is transcriptionally activated by YY1 and regulates the stability of TRAM2 mRNA in an m6A-dependent manner. Overall, our results reveal a YY1-RBM15B-TRAM2 regulatory axis and highlight the critical role of RBM15B and m6A modifications in HCC. These findings may provide a novel mechanism and therapeutic targets for the treatment of HCC.
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Affiliation(s)
- Chunzhong Tan
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Department of Translational Medicine Research Center, Wuhan University, Wuhan, China
| | - Peng Xia
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Department of Translational Medicine Research Center, Wuhan University, Wuhan, China
| | - Hao Zhang
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Department of Translational Medicine Research Center, Wuhan University, Wuhan, China
| | - Kequan Xu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Department of Translational Medicine Research Center, Wuhan University, Wuhan, China
| | - Pengpeng Liu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Deliang Guo
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
| | - Zhisu Liu
- Department of Hepatobiliary & Pancreatic Surgery, Zhongnan Hospital of Wuhan University, Wuhan, China
- Department of Translational Medicine Research Center, Wuhan University, Wuhan, China
- *Correspondence: Zhisu Liu,
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10
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Takeda T, Yamamoto Y, Tsubaki M, Matsuda T, Kimura A, Shimo N, Nishida S. PI3K/Akt/YAP signaling promotes migration and invasion of DLD‑1 colorectal cancer cells. Oncol Lett 2022; 23:106. [DOI: 10.3892/ol.2022.13226] [Citation(s) in RCA: 0] [Impact Index Per Article: 0] [Reference Citation Analysis] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 10/26/2021] [Accepted: 01/25/2022] [Indexed: 12/24/2022] Open
Affiliation(s)
- Tomoya Takeda
- Division of Pharmacotherapy, Kindai University School of Pharmacy, Higashi‑Osaka, Osaka 577‑8502, Japan
| | - Yuuta Yamamoto
- Division of Pharmacotherapy, Kindai University School of Pharmacy, Higashi‑Osaka, Osaka 577‑8502, Japan
| | - Masanobu Tsubaki
- Division of Pharmacotherapy, Kindai University School of Pharmacy, Higashi‑Osaka, Osaka 577‑8502, Japan
| | - Takuya Matsuda
- Division of Pharmacotherapy, Kindai University School of Pharmacy, Higashi‑Osaka, Osaka 577‑8502, Japan
| | - Akihiro Kimura
- Division of Pharmacotherapy, Kindai University School of Pharmacy, Higashi‑Osaka, Osaka 577‑8502, Japan
| | - Natsumi Shimo
- Division of Pharmacotherapy, Kindai University School of Pharmacy, Higashi‑Osaka, Osaka 577‑8502, Japan
| | - Shozo Nishida
- Division of Pharmacotherapy, Kindai University School of Pharmacy, Higashi‑Osaka, Osaka 577‑8502, Japan
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Gao X, Jiang W, Ke Z, Huang Q, Chen L, Zhang G, Li C, Yu X. TRAM2 promotes the malignant progression of glioma through PI3K/AKT/mTOR pathway. Biochem Biophys Res Commun 2022; 586:34-41. [PMID: 34826698 DOI: 10.1016/j.bbrc.2021.11.061] [Citation(s) in RCA: 7] [Impact Index Per Article: 2.3] [Reference Citation Analysis] [Abstract] [Key Words] [MESH Headings] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/26/2021] [Revised: 11/08/2021] [Accepted: 11/15/2021] [Indexed: 01/18/2023]
Abstract
Molecular biomarkers play an important guidance role in the diagnosis and treatment of glioma. It has been found that TRAM2 (translocation associated membrane protein 2) drives human cancers development. Here we report that TRAM2 activity is required for malignancy properties of glioma. In this study, we demonstrated that TRAM2 is over-expressed in glioma and cell lines, particularly in the mesenchymal subtype, and glioma patients with high expression of TRAM2 is associated with poorer survival. Silencing of TRAM2 significantly suppresses glioma cell proliferation, invasion, migration and EMT in vitro, and inhibits tumorigenicity of glioma cell in vivo. We further identify that TRAM2 is positively associated with activation of the PI3K/AKT/mTOR signaling in glioma. 740Y-P, a PI3K activator, reversed the effects of TRAM2 silencing on glioma cell proliferation, invasion, migration and EMT process. Taken together, these findings establish that TRAM2/PI3K/AKT/mTOR signaling drives malignancy properties of glioma and indicate that TRAM2 may act as a potential therapeutic target for glioma.
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Affiliation(s)
- Xiang Gao
- Department of Neurosurgery, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, 332000, China; Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, 332000, China.
| | - Wenqu Jiang
- Department of Neurosurgery, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, 332000, China; Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, 332000, China
| | - Zunliang Ke
- Department of Neurosurgery, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, 332000, China; Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, 332000, China
| | - Qiwei Huang
- Department of Neurosurgery, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, 332000, China; Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, 332000, China
| | - Liang Chen
- Department of Neurosurgery, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, 332000, China; Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, 332000, China
| | - Guobin Zhang
- Department of Neurosurgery, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, 332000, China; Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, 332000, China
| | - Chao Li
- Department of Neurosurgery, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, 332000, China; Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, 332000, China
| | - Xiaojun Yu
- Department of Neurosurgery, Affiliated Hospital of Jiujiang University, Jiujiang, Jiangxi, 332000, China; Jiujiang Clinical Precision Medicine Research Center, Jiujiang, Jiangxi, 332000, China
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12
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Lopez-Hernandez A, Sberna S, Campaner S. Emerging Principles in the Transcriptional Control by YAP and TAZ. Cancers (Basel) 2021; 13:cancers13164242. [PMID: 34439395 PMCID: PMC8391352 DOI: 10.3390/cancers13164242] [Citation(s) in RCA: 23] [Impact Index Per Article: 5.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 07/23/2021] [Revised: 08/13/2021] [Accepted: 08/15/2021] [Indexed: 12/12/2022] Open
Abstract
Simple Summary YAP and TAZ are transcriptional cofactors that integrate several upstream signals to generate context-dependent transcriptional responses. This requires extensive integration with epigenetic regulators and other transcription factors. The molecular and genomic characterization of YAP and TAZ nuclear function has broad implications both in physiological and pathological settings. Abstract Yes-associated protein (YAP) and TAZ are transcriptional cofactors that sit at the crossroad of several signaling pathways involved in cell growth and differentiation. As such, they play essential functions during embryonic development, regeneration, and, once deregulated, in cancer progression. In this review, we will revise the current literature and provide an overview of how YAP/TAZ control transcription. We will focus on data concerning the modulation of the basal transcriptional machinery, their ability to epigenetically remodel the enhancer–promoter landscape, and the mechanisms used to integrate transcriptional cues from multiple pathways. This reveals how YAP/TAZ activation in cancer cells leads to extensive transcriptional control that spans several hallmarks of cancer. The definition of the molecular mechanism of transcriptional control and the identification of the pathways regulated by YAP/TAZ may provide therapeutic opportunities for the effective treatment of YAP/TAZ-driven tumors.
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13
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Dieter SM, Siegl C, Codó PL, Huerta M, Ostermann-Parucha AL, Schulz E, Zowada MK, Martin S, Laaber K, Nowrouzi A, Blatter M, Kreth S, Westermann F, Benner A, Uhrig U, Putzker K, Lewis J, Haegebarth A, Mumberg D, Holton SJ, Weiske J, Toepper LM, Scheib U, Siemeister G, Ball CR, Kuster B, Stoehr G, Hahne H, Johannes S, Lange M, Herbst F, Glimm H. Degradation of CCNK/CDK12 is a druggable vulnerability of colorectal cancer. Cell Rep 2021; 36:109394. [PMID: 34289372 DOI: 10.1016/j.celrep.2021.109394] [Citation(s) in RCA: 47] [Impact Index Per Article: 11.8] [Reference Citation Analysis] [Abstract] [Key Words] [Track Full Text] [Journal Information] [Subscribe] [Scholar Register] [Received: 09/23/2020] [Revised: 04/08/2021] [Accepted: 06/23/2021] [Indexed: 02/07/2023] Open
Abstract
Novel treatment options for metastatic colorectal cancer (CRC) are urgently needed to improve patient outcome. Here, we screen a library of non-characterized small molecules against a heterogeneous collection of patient-derived CRC spheroids. By prioritizing compounds with inhibitory activity in a subset of-but not all-spheroid cultures, NCT02 is identified as a candidate with minimal risk of non-specific toxicity. Mechanistically, we show that NCT02 acts as molecular glue that induces ubiquitination of cyclin K (CCNK) and proteasomal degradation of CCNK and its complex partner CDK12. Knockout of CCNK or CDK12 decreases proliferation of CRC cells in vitro and tumor growth in vivo. Interestingly, sensitivity to pharmacological CCNK/CDK12 degradation is associated with TP53 deficiency and consensus molecular subtype 4 in vitro and in patient-derived xenografts. We thus demonstrate the efficacy of targeted CCNK/CDK12 degradation for a CRC subset, highlighting the potential of drug-induced proteolysis for difficult-to-treat types of cancer.
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Affiliation(s)
- Sebastian M Dieter
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany.
| | | | - Paula L Codó
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany; CureVac AG, 60325 Frankfurt am Main, Germany
| | - Mario Huerta
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany
| | - Anna L Ostermann-Parucha
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany
| | - Erik Schulz
- Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, 69120 Heidelberg, Germany
| | - Martina K Zowada
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
| | - Sylvia Martin
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany
| | - Karin Laaber
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany; Faculty of Biosciences, Heidelberg University, 69120 Heidelberg, Germany
| | - Ali Nowrouzi
- Division of Molecular and Translational Radiation Oncology, Heidelberg Medical Faculty, Heidelberg University, 69120 Heidelberg, Germany
| | - Mona Blatter
- Hopp Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Neuroblastoma Genomics, DKFZ Heidelberg, 69120 Heidelberg, Germany
| | - Sina Kreth
- Hopp Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Neuroblastoma Genomics, DKFZ Heidelberg, 69120 Heidelberg, Germany
| | - Frank Westermann
- Hopp Children's Cancer Center Heidelberg (KiTZ), 69120 Heidelberg, Germany; Division of Neuroblastoma Genomics, DKFZ Heidelberg, 69120 Heidelberg, Germany
| | - Axel Benner
- Division of Biostatistics, DKFZ Heidelberg, 69120 Heidelberg, Germany
| | - Ulrike Uhrig
- European Molecular Biology Laboratory (EMBL), Chemical Biology Core Facility, 69117 Heidelberg, Germany
| | - Kerstin Putzker
- European Molecular Biology Laboratory (EMBL), Chemical Biology Core Facility, 69117 Heidelberg, Germany
| | - Joe Lewis
- European Molecular Biology Laboratory (EMBL), Chemical Biology Core Facility, 69117 Heidelberg, Germany
| | - Andrea Haegebarth
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany
| | - Dominik Mumberg
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany
| | - Simon J Holton
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany; Nuvisan Innovation Campus Berlin GmbH, 13353 Berlin, Germany
| | - Joerg Weiske
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany; Nuvisan Innovation Campus Berlin GmbH, 13353 Berlin, Germany
| | - Lena-Marit Toepper
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany; Nuvisan Innovation Campus Berlin GmbH, 13353 Berlin, Germany
| | - Ulrike Scheib
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany; Nuvisan Innovation Campus Berlin GmbH, 13353 Berlin, Germany
| | - Gerhard Siemeister
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany; Nuvisan Innovation Campus Berlin GmbH, 13353 Berlin, Germany
| | - Claudia R Ball
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 01307 Dresden, Germany; Center for Personalized Oncology, University Hospital Carl Gustav Carus Dresden at TU Dresden, 01307 Dresden, Germany
| | - Bernhard Kuster
- Chair of Proteomics and Bioanalytics, Technical University of Munich, 85354 Freising, Germany
| | | | | | - Sarah Johannes
- Bayer AG, Research & Development, Pharmaceuticals, 42117 Wuppertal, Germany
| | - Martin Lange
- Bayer AG, Research & Development, Pharmaceuticals, 13353 Berlin, Germany; Nuvisan Innovation Campus Berlin GmbH, 13353 Berlin, Germany
| | - Friederike Herbst
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany
| | - Hanno Glimm
- Department of Translational Medical Oncology, National Center for Tumor Diseases (NCT) Dresden and German Cancer Research Center (DKFZ), 01307 Dresden, Germany; Translational Functional Cancer Genomics, NCT and DKFZ Heidelberg, 69120 Heidelberg, Germany; German Cancer Consortium (DKTK), 01307 Dresden, Germany; Center for Personalized Oncology, University Hospital Carl Gustav Carus Dresden at TU Dresden, 01307 Dresden, Germany.
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14
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Concurrent YAP/TAZ and SMAD signaling mediate vocal fold fibrosis. Sci Rep 2021; 11:13484. [PMID: 34188130 PMCID: PMC8241934 DOI: 10.1038/s41598-021-92871-z] [Citation(s) in RCA: 20] [Impact Index Per Article: 5.0] [Reference Citation Analysis] [Abstract] [Track Full Text] [Download PDF] [Figures] [Journal Information] [Subscribe] [Scholar Register] [Received: 03/17/2021] [Accepted: 06/10/2021] [Indexed: 01/17/2023] Open
Abstract
Vocal fold (VF) fibrosis is a major cause of intractable voice-related disability and reduced quality of life. Excision of fibrotic regions is suboptimal and associated with scar recurrence and/or further iatrogenic damage. Non-surgical interventions are limited, putatively related to limited insight regarding biochemical events underlying fibrosis, and downstream, the lack of therapeutic targets. YAP/TAZ integrates diverse cell signaling events and interacts with signaling pathways related to fibrosis, including the TGF-β/SMAD pathway. We investigated the expression of YAP/TAZ following vocal fold injury in vivo as well as the effects of TGF-β1 on YAP/TAZ activity in human vocal fold fibroblasts, fibroblast-myofibroblast transition, and TGF-β/SMAD signaling. Iatrogenic injury increased nuclear localization of YAP and TAZ in fibrotic rat vocal folds. In vitro, TGF-β1 activated YAP and TAZ in human VF fibroblasts, and inhibition of YAP/TAZ reversed TGF-β1-stimulated fibroplastic gene upregulation. Additionally, TGF-β1 induced localization of YAP and TAZ in close proximity to SMAD2/3, and nuclear accumulation of SMAD2/3 was inhibited by a YAP/TAZ inhibitor. Collectively, YAP and TAZ were synergistically activated with the TGF-β/SMAD pathway, and likely essential for the fibroplastic phenotypic shift in VF fibroblasts. Based on these data, YAP/TAZ may evolve as an attractive therapeutic target for VF fibrosis.
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