SIRT1 regulates YAP2-mediated cell proliferation and chemoresistance in hepatocellular carcinoma
SIRT1 regulates YAP2-mediated cell proliferation and chemoresistance in hepatocellular carcinoma
复制标题
SIRT1 调节 YAP2 介导的肝细胞癌细胞增殖和化疗耐药。
作者：
Mao, B.;Hu, F.;Bi, W.
MST/雅普（mammalian Ste 20-like kinase/Yes-associated protein 2）通路在肝细胞癌（HCC）的发生发展中起着重要作用。虽然翻译后修饰，特别是MST/Lats（大肿瘤抑制因子）介导的磷酸化和PP 1（蛋白磷酸酶-1）介导的去磷酸化已被发现调节YAP 2的活性，很少有人知道它的乙酰化。在我们的实验中，我们观察到SIRT 1在肝癌患者的肿瘤样品中的表达显著上调，并且SIRT 1 mRNA水平与结缔组织生长因子（CTGF）mRNA水平呈正相关。然后我们发现，SIRT 1使HCC细胞中的YAP 2蛋白脱乙酰化，SIRT 1介导的脱乙酰化增加了YAP 2/TEAD 4的结合，导致YAP 2/TEAD 4转录激活和HCC细胞生长上调。此外，SIRT 1的敲低阻断顺铂（CDDP）诱导的YAP 2核转位，并增强HCC细胞对CDDP治疗的化疗敏感性。总之，我们的研究结果揭示了一种新的调节机制，YAP 2通过SIRT 1介导的脱乙酰化，可能参与肝癌的发生和耐药性。
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.