CSN6-SPOP-HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation.

Advanced science (Weinheim, Baden-Wurttemberg, Germany) 2024 Apr

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Cholesterol metabolism has important roles in maintaining membrane integrity and countering the development of diseases such as obesity and cancers. Cancer cells sustain cholesterol biogenesis for their proliferation and microenvironment reprograming even when sterols are abundant. However, efficacy of targeting cholesterol metabolism for cancer treatment is always compromised. Here it is shown that CSN6 is elevated in HCC and is a positive regulator of hydroxymethylglutaryl-CoA synthase 1 (HMGCS1) of mevalonate (MVA) pathway to promote tumorigenesis. Mechanistically, CSN6 antagonizes speckle-type POZ protein (SPOP) ubiquitin ligase to stabilize HMGCS1, which in turn activates YAP1 to promote tumor growth. In orthotopic liver cancer models, targeting CSN6 and HMGCS1 hinders tumor growth in both normal and high fat diet. Significantly, HMGCS1 depletion improves YAP inhibitor efficacy in patient derived xenograft models. The results identify a CSN6-HMGCS1-YAP1 axis mediating tumor outgrowth in HCC and propose a therapeutic strategy of targeting non-alcoholic fatty liver diseases- associated HCC. © 2024 The Authors. Advanced Science published by Wiley‐VCH GmbH.

Citation

Kai Li, Jiayu Zhang, Haiwen Lyu, Jinneng Yang, Wenxia Wei, Yuzhi Wang, Haidan Luo, Yijing Zhang, Xin Jiang, Hairong Yi, Mengan Wang, Caiyun Zhang, Kang Wu, Lishi Xiao, Weijie Wen, Hui Xu, Guolin Li, Yunle Wan, Fang Yang, Runxiang Yang, Xinhui Fu, Baifu Qin, Zhongguo Zhou, Haipeng Zhang, Mong-Hong Lee. CSN6-SPOP-HMGCS1 Axis Promotes Hepatocellular Carcinoma Progression via YAP1 Activation. Advanced science (Weinheim, Baden-Wurttemberg, Germany). 2024 Apr;11(14):e2306827