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

May 3, 2021

Contributor: 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.

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.

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About The Expert

Qiang Pan

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.

Shanshan Zhong

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.

Hanling Wang

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.

Xuege Wang

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.

Ni Li

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.

Yaqi Li

Department of Colorectal Surgery, Fudan University Shanghai Cancer Center, Shanghai 200032, China; Department of Oncology, Shanghai Medical College, Fudan University, Shanghai 200032, China.

Guoying Zhang

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.

Huairui Yuan

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.

Yannan Lian

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.

Qilong Chen

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.

Ying Han

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.

Jiacheng Guo

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.

Qiuli Liu

Department of Urology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China.

Tong Qiu

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.

Jun Jiang

Department of Urology, Institute of Surgery Research, Daping Hospital, Army Medical University, Chongqing 400042, China.

Qintong Li

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.

Minjia Tan

State Key Laboratory of Drug Research, Shanghai Institute of Materia Medica, Chinese Academy of Sciences, Shanghai 201203, China.

Huiyong Yin

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.

Junjie Peng

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.

Yichuan Xiao

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.

Jun Qin

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.

References

PubMed