CAS Key Laboratory of Tissue Microenvironment and Tumor, CAS Center for Excellence in Molecular Cell Science, Shanghai Institute of Nutrition and Health, Shanghai Jiao Tong University School of Medicine (SJTUSM) & Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
CAS Key Laboratory of Nutrition, Metabolism and Food Safety, Shanghai Institute of Nutrition and Health, University of Chinese Academy of Sciences, Chinese Academy of Sciences, 320 Yueyang Road, Shanghai 200031, China.
Mol Cell. 2021 Jul 1;81(13):2736-2751.e8. doi: 10.1016/j.molcel.2021.04.009. Epub 2021 Apr 30.
Cholesterol metabolism is tightly associated with colorectal cancer (CRC). Nevertheless, the clinical benefit of statins, the inhibitor of cholesterol biogenesis mevalonate (MVA) pathway, is inconclusive, possibly because of a lack of patient stratification criteria. Here, we describe that YAP-mediated zinc finger MYND-type containing 8 (ZMYND8) expression sensitizes intestinal tumors to the inhibition of the MVA pathway. We show that the oncogenic activity of YAP relies largely on ZMYND8 to enhance intracellular de novo cholesterol biogenesis. Disruption of the ZMYND8-dependent MVA pathway greatly restricts the self-renewal capacity of Lgr5 intestinal stem cells (ISCs) and intestinal tumorigenesis. Mechanistically, ZMYND8 and SREBP2 drive the enhancer-promoter interaction to facilitate the recruitment of Mediator complex, thus upregulating MVA pathway genes. Together, our results establish that the epigenetic reader ZMYND8 endows YAP-high intestinal cancer with metabolic vulnerability.
胆固醇代谢与结直肠癌（CRC）密切相关。然而，胆固醇生物合成甲羟戊酸（MVA）途径抑制剂他汀类药物的临床获益尚不确定，可能是因为缺乏患者分层标准。在这里，我们描述了 YAP 介导的锌指 MYND 型包含 8 （ZMYND8）表达使肠道肿瘤对 MVA 途径抑制敏感。我们表明，YAP 的致癌活性在很大程度上依赖于 ZMYND8 来增强细胞内从头胆固醇生物合成。破坏依赖 ZMYND8 的 MVA 途径极大地限制了 Lgr5 肠干细胞（ISCs）的自我更新能力和肠道肿瘤发生。在机制上，ZMYND8 和 SREBP2 驱动增强子-启动子相互作用，从而促进中介复合物的募集，从而上调 MVA 途径基因。总之，我们的结果表明，表观遗传阅读器 ZMYND8 赋予 YAP 高肠道癌代谢脆弱性。
