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 upregulating MVA pathway genes. Together, our results establish that the epigenetic reader ZMYND8 endows YAP-high intestinal cancer with metabolic vulnerability. [Display omitted] • ZMYND8-mediated MVA biogenesis promotes intestinal stemness and tumorigenesis • ZMYND8/SREBP2-coordinated enhancer-promoter interaction activates the MVA pathway • YAP stimulates cholesterol biogenesis via ZMYND8 Pan et al. uncover a metabolic addiction of the MVA pathway in YAP-driven tumors. The identified YAP target gene ZMYND8 interacts with SERBP2 to enable enhancer-promoter communication to upregulate the MVA pathway. These findings provide a rationale to use MVA pathway inhibitors (statins) to treat the tumors with YAP-high activity. [ABSTRACT FROM AUTHOR]