SDHA/B reduction promotes hepatocellular carcinoma by facilitating the deNEDDylation of cullin1 and stabilizing YAP/TAZ

作者：Tao Yuan, Tianyi Zhou, Meijia Qian, Jiamin Du, Yue Liu, Jia’er Wang, Yonghao Li, Guanghan Fan, Fangjie Yan, Xiaoyang Dai, Xiawei Li, Yulian Wu, Xin Dong, Qiaojun He, Hong Zhu, Bo Yang · 发表于：Hepatology · 年份：2022 · DOI：10.1002/hep.32621 · 被引用次数：32 · 研究领域：Hippo pathway signaling and YAP/TAZ、Protein Degradation and Inhibitors、Cancer, Hypoxia, and Metabolism

BACKGROUND AND AIMS: Succinate dehydrogenase enzyme (SDH) is frequently diminished in samples from patients with hepatocellular carcinoma (HCC), and SDH reduction is associated with elevated succinate level and poor prognosis in patients with HCC. However, the underlying mechanisms of how impaired SDH activity promotes HCC remain unclear. APPROACH AND RESULTS: In this study, we observed remarkable downregulations of SDH subunits A and B (SDHA/B) in chronic liver injury-induced murine HCC models and patient samples. Subsequent RNA sequencing, hematoxylin and eosin staining, and immunohistochemistry analyses of HCC samples revealed that Yes-associated protein (YAP) and transcriptional coactivator with PDZ-binding motif (TAZ) were significantly upregulated in HCC, with their levels inversely correlating with that of SDHA/B. YAP/TAZ stability was greatly enhanced in SDHA/B-depleted HCC cells along with accumulation of succinate. Further mechanistic analyses demonstrated that impaired activity of SDHA/B resulted in succinate accumulation, which facilitated the deNEDDylation of cullin1 and therefore disrupted the E3 ubiquitin ligase SCF β-TrCP complex, consequently leading to YAP/TAZ stabilization and activation in HCC cells. The accelerated in vitro cell proliferation and in vivo tumor growth caused by SDHA/B reduction or succinate exposure were largely dependent on the aberrant activation of YAP/TAZ. CONCLUSIONS: Our study demonstrated that SDHA/B reduction promotes HCC prolifera...