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

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 up regulating MVA pathway genes. Together, our results establish that the epigenetic reader ZMYND8 endows YAP-high intestinal cancer with metabolic vulnerability.

Automated summary

Cholesterol metabolism is closely related to colorectal cancer, but the clinical benefit of statins in inhibiting the mevalonate pathway is uncertain. This study reveals that ZMYND8 plays a crucial role in enhancing de novo cholesterol biosynthesis and promoting the growth of intestinal tumors with high YAP expression.