The ZMYND8-regulated mevalonate pathway endows YAP-high intestinal cancer with metabolic vulnerability.

Molecular cell 2021 Jul 01

filter terms:

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. Copyright © 2021 Elsevier Inc. All rights reserved.

Citation

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. The ZMYND8-regulated mevalonate pathway endows YAP-high intestinal cancer with metabolic vulnerability. Molecular cell. 2021 Jul 01;81(13):2736-2751.e8