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SIRT1 regulates YAP2-mediated cell proliferation and chemoresistance in hepatocellular carcinoma

Oncogene volume 33, pages 1468–1474 (2014)Cite this article

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Abstract

The MST/YAP (mammalian Ste20-like kinase/Yes-associated protein 2) pathway plays an important role in hepatocellular carcinoma (HCC). Although post-translational modification—especially MST/Lats (large tumor suppressor)-mediated phosphorylation and PP1 (protein phosphatase-1)-mediated dephosphorylation—has been found to regulate the activity of YAP2, very little is known about its acetylation. In our experiments, we observed that the expression of SIRT1 is significantly upregulated in the tumor samples of the hepatocarcinoma patients, and SIRT1 mRNA level positively correlates with connective tissue growth factor (CTGF) mRNA level. We then found that SIRT1 deacetylates YAP2 protein in HCC cells and SIRT1-mediated deacetylation increases the YAP2/TEAD4 association, leading to YAP2/TEAD4 transcriptional activation and upregulated cell growth in HCC cells. Moreover, knockdown of SIRT1 blocks the cisplatin (CDDP)-induced nuclear translocation of YAP2 and enhances the chemosensitivity of HCC cells to CDDP treatment. Together, our findings reveal a new regulatory mechanism of YAP2 by the SIRT1-mediated deacetylation that may be involved in HCC tumorigenesis and drug resistance.

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Abbreviations

HCC:

hepatocellular carcinoma

NAD:

nicotinamide adenine dinucleotide

YAP2:

Yes-associated protein 2.

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Acknowledgements

We thank Dr Depei Liu for the gift of all the SIRT1 plasmids; Dr Lei Zhang for the 3*SD binding site artificial-luciferase reporter plasmid; Dr Zhixiong Xiao for the p73 antibody; Ursula Adams for manuscript editing; and Xudong Zhao and Su Liu of IBP core facility center for technical support. This work was supported by the National Science Foundation of China (81172553, 81201564, 81125010 and 81030025), and the Ministry of Science and Technology of China (973-2009CB918704 and 973-2012CB910701).

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  1. B Mao and F Hu: These authors contributted equally to this work.

Authors and Affiliations

  1. Institute of Biophysics, Chinese Academy of Sciences, Beijing, China

    B Mao, J Cheng, P Wang & Z Yuan

  2. Department of Orthopedics, Tianjin Hospital, Tianjin, China

    F Hu

  3. Department of Orthopedics, Clinical Division of Surgery, Chinese PLA General Hospital, Beijing, China

    M Xu, F Yuan, Y Wang & W Bi

  4. Institute of Cancer Stem Cell, Dalian Medical University Cancer Center, Dalian, China

    S Meng

  5. The Chinese Hippo Consortium, China

    S Meng & Z Yuan

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  1. B Mao
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Correspondence to Z Yuan or W Bi.

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Mao, B., Hu, F., Cheng, J. et al. SIRT1 regulates YAP2-mediated cell proliferation and chemoresistance in hepatocellular carcinoma. Oncogene 33, 1468–1474 (2014). https://doi.org/10.1038/onc.2013.88

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