生物
LGR5型
表观遗传学
增强子
生物发生
调解人
细胞生物学
癌症研究
癌症
Wnt信号通路
信号转导
转录因子
遗传学
癌变
基因
作者
Qiang Pan,Shanshan Zhong,Hanling Wang,Xuege Wang,Ni Li,Yaqi Li,Guoying Zhang,Huairui Yuan,Yannan Lian,Qilong Chen,Ying Han,Jiacheng Guo,Qiuli Liu,Tong Qiu,Jun Jiang,Qintong Li,Minjia Tan,Huiyong Yin,Junjie Peng,Yichuan Xiao,Jun Qin
出处
期刊:Molecular Cell
[Elsevier]
日期:2021-07-01
卷期号:81 (13): 2736-2751.e8
被引量:19
标识
DOI:10.1016/j.molcel.2021.04.009
摘要
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.
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