Loss of SPTBN1 Suppresses Autophagy Via SETD7-mediated YAP Methylation in Hepatocellular Carcinoma Initiation and Development

作者：Shuyi Chen, Huijie Wu, Zhengyang Wang, Mengping Jia, Jieyu Guo, Jiayu Jin, Xiaobo Li, Dan Meng, Ling Lin, Aiwu Ruth He, Ping Zhou, Xiuling Zhi · 发表于：Cellular and Molecular Gastroenterology and Hepatology · 年份：2021 · DOI：10.1016/j.jcmgh.2021.10.012 · 被引用次数：25 · 研究领域：Hippo pathway signaling and YAP/TAZ、Autophagy in Disease and Therapy、Epigenetics and DNA Methylation

BACKGROUND & AIMS: Loss of Spectrin beta, non-erythrocytic 1 (SPTBN1) plays an important role in the carcinogenesis of hepatocellular carcinoma (HCC); however, the mechanisms underlying its involvement remain poorly understood. Defects in autophagy contribute to hepatic tumor formation. Hence, in this study, we explored the role and mechanism of SPTBN1 in the autophagy of hepatic stem cells (HSCs) and HCC cells. METHODS: mice induced by 3,5-diethoxycarbonyl-1,4-dihydrocollidine treatment. Hippo pathway and Yes-associated protein (YAP) stabilization were examined in isolated HSCs, Huh-7, and PLC/PRF/5 HCC cells and hepatocytes with or without loss of SPTBN1. RESULTS: We found that heterozygous SPTBN1 knockout accelerated liver tumor development with 3,5-diethoxycarbonyl-1,4-dihydrocollidine induction. Rapamycin promoted autophagy in murine HSCs and reversed the increased malignant transformation induced by heterozygous SPTBN1 deletion. Loss of SPTBN1 also decreased autophagy and increased YAP stability and nuclear localization in human HCC cells and tissues, whereas YAP inhibition attenuated the effects of SPTBN1 deficiency on autophagy. Finally, we found that SPTBN1 positively regulated the expression of suppressor of variegation 3-9-enhancer of zeste-trithorax domain containing lysine methyltransferase 7 to promote YAP methylation, which may lead to YAP degradation and inactivation. CONCLUSIONS: Our findings provide the first demonstration that loss of SPTBN1 impairs autopha...