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Transcriptional Enhancer Factor Domain Family member 4 Exerts an Oncogenic Role in Hepatocellular Carcinoma by Hippo-Independent Regulation of Heat Shock Protein 70 Family Members

Coto-Llerena, Mairene and Tosti, Nadia and Taha-Mehlitz, Stephanie and Kancherla, Venkatesh and Paradiso, Viola and Gallon, John and Bianco, Gaia and Garofoli, Andrea and Ghosh, Souvik and Tang, Fengyuan and Ercan, Caner and Christofori, Gerhard M. and Matter, Matthias S. and Droeser, Raoul A. and Zavolan, Mihaela and Soysal, Savas D. and von Flüe, Markus and Kollmar, Otto and Terracciano, Luigi M. and Ng, Charlotte K. Y. and Piscuoglio, Salvatore. (2021) Transcriptional Enhancer Factor Domain Family member 4 Exerts an Oncogenic Role in Hepatocellular Carcinoma by Hippo-Independent Regulation of Heat Shock Protein 70 Family Members. Hepatology Communications, 5 (4). pp. 661-674.

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Official URL: https://edoc.unibas.ch/81594/

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Abstract

Transcriptional enhancer factor domain family member 4 (TEAD4) is a downstream effector of the conserved Hippo signaling pathway, regulating the expression of genes involved in cell proliferation and differentiation. It is up-regulated in several cancer types and is associated with metastasis and poor prognosis. However, its role in hepatocellular carcinoma (HCC) remains largely unexplored. Using data from The Cancer Genome Atlas, we found that TEAD4 was overexpressed in HCC and was associated with aggressive HCC features and worse outcome. Overexpression of TEAD4 significantly increased proliferation and migration rates in HCC cells in vitro as well as tumor growth in vivo. Additionally, RNA sequencing analysis of TEAD4-overexpressing HCC cells demonstrated that TEAD4 overexpression was associated with the up-regulation of genes involved in epithelial-to-mesenchymal transition, proliferation, and protein-folding pathways. Among the most up-regulated genes following TEAD4 overexpression were the 70-kDa heat shock protein (HSP70) family members HSPA6 and HSPA1A. Chromatin immunoprecipitation-quantitative real-time polymerase chain reaction experiments demonstrated that TEAD4 regulates HSPA6 and HSPA1A expression by directly binding to their promoter and enhancer regions. The pharmacologic inhibition of HSP70 expression in TEAD4-overexpressing cells reduced the effect of TEAD4 on cell proliferation. Finally, by overexpressing TEAD4 in yes-associated protein (YAP)/transcriptional coactivator with PDZ binding motif (TAZ)-knockdown HCC cells, we showed that the effect of TEAD4 on cell proliferation and its regulation of HSP70 expression does not require YAP and TAZ, the main effectors of the Hippo signaling pathway. Conclusion: A novel Hippo-independent mechanism for TEAD4 promotes cell proliferation and tumor growth in HCC by directly regulating HSP70 family members.
Faculties and Departments:03 Faculty of Medicine > Bereich Operative Fächer (Klinik) > Innere Organe > Viszeralchirurgie Clarunis (von Flüe)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Operative Fächer (Klinik) > Innere Organe > Viszeralchirurgie Clarunis (von Flüe)
03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Pathologie USB
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Querschnittsfächer (Klinik) > Pathologie USB
03 Faculty of Medicine > Bereich Querschnittsfächer (Klinik) > Pathologie USB > Molekulare Pathologie (Terracciano)
03 Faculty of Medicine > Departement Klinische Forschung > Bereich Querschnittsfächer (Klinik) > Pathologie USB > Molekulare Pathologie (Terracciano)
03 Faculty of Medicine > Departement Biomedizin
03 Faculty of Medicine > Departement Biomedizin > Division of Biochemistry and Genetics > Tumor Biology (Christofori)
05 Faculty of Science > Departement Biozentrum > Computational & Systems Biology > Bioinformatics (Zavolan)
UniBasel Contributors:Zavolan, Mihaela and Ghosh, Souvik and Tosti, Nadia and Taha-Mehlitz, Stephanie Gerda Erika and Venkatesh, Kancherla and Paradiso, Viola and Gallon, John and Bianco, Gaia and Garofoli, Andrea and Tang, Fengyuan and Ercan, Caner and Christofori, Gerhard M. and Matter, Matthias and Droeser, Raoul and Soysal, Savas Deniz and von Flüe, Markus and Kollmar, Otto and Ng, Kiu Yan Charlotte and Piscuoglio, Salvatore and Terracciano, Luigi M.
Item Type:Article, refereed
Article Subtype:Research Article
Publisher:Wiley
ISSN:2471-254X
Note:Publication type according to Uni Basel Research Database: Journal article
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Last Modified:31 Aug 2021 09:03
Deposited On:31 Aug 2021 09:03

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