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

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

doi:10.1016/j.molcel.2021.04.009

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

Mol Cell. 2021 Jul 1;81(13):2736-2751.e8. doi: 10.1016/j.molcel.2021.04.009. Epub 2021 Apr 30.

Authors

Qiang Pan¹, Shanshan Zhong², Hanling Wang¹, Xuege Wang¹, Ni Li¹, Yaqi Li³, Guoying Zhang¹, Huairui Yuan¹, Yannan Lian¹, Qilong Chen¹, Ying Han¹, Jiacheng Guo¹, Qiuli Liu⁴, Tong Qiu⁵, Jun Jiang⁴, Qintong Li⁵, Minjia Tan⁶, Huiyong Yin², Junjie Peng⁷, Yichuan Xiao⁸, Jun Qin⁹

Affiliations

¹ 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.
² 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.
³ Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.
⁴ Department of Urology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China.
⁵ Department of Obstetrics, Gynecology and Pediatrics, West China Second University Hospital, Key Laboratory of Birth Defects and Related Diseases of Women and Children, Ministry of Education, Sichuan University, 20 Renmin South Road, Chengdu 610041, China.
⁶ State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.
⁷ Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China. Electronic address: pengjj67@hotmail.com.
⁸ 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. Electronic address: ycxiao@sibs.ac.cn.
⁹ 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. Electronic address: qinjun@sibs.ac.cn.

PMID: 33932349
DOI: 10.1016/j.molcel.2021.04.009

Abstract

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.

Keywords: Colorectal cancer; Enhancer-promoter contact; Intestinal stem cell (ISC); Mevalonate (MVA) pathway; YAP; ZMYND8.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adaptor Proteins, Signal Transducing / genetics
Adaptor Proteins, Signal Transducing / metabolism*
Animals
Cell Line, Tumor
Colorectal Neoplasms / genetics
Colorectal Neoplasms / metabolism*
Colorectal Neoplasms / pathology
Mevalonic Acid / metabolism*
Mice
Mice, Transgenic
Tumor Suppressor Proteins / genetics
Tumor Suppressor Proteins / metabolism*
YAP-Signaling Proteins

Substances

Adaptor Proteins, Signal Transducing
Tumor Suppressor Proteins
YAP-Signaling Proteins
Yap1 protein, mouse
Zmynd8 protein, mouse
Mevalonic Acid