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

被引：37

作者：

Pan, Qiang ^{[1
,2
]}

Zhong, Shanshan ^{[3
]}

Wang, Hanling ^{[1
,2
]}

Wang, Xuege ^{[1
,2
]}

Li, Ni ^{[1
,2
]}

Li, Yaqi ^{[4
,5
]}

Zhang, Guoying ^{[1
,2
]}

Yuan, Huairui ^{[1
,2
]}

Lian, Yannan ^{[1
,2
]}

Chen, Qilong ^{[1
,2
]}

Han, Ying ^{[1
,2
]}

Guo, Jiacheng ^{[1
,2
]}

Liu, Qiuli ^{[6
]}

Qiu, Tong ^{[7
]}

Jiang, Jun ^{[6
]}

Li, Qintong ^{[7
]}

Tan, Minjia ^{[8
]}

Yin, Huiyong ^{[3
]}

Peng, Junjie ^{[4
,5
]}

Xiao, Yichuan ^{[1
,2
]}

Qin, Jun ^{[1
,2
]}

机构：

[1] Shanghai Jiao Tong Univ, Shanghai Inst Nutr & Hlth, CAS Ctr Excellence Mol Cell Sci, CAS Key Lab Tissue Microenvironm & Tumor,Sch Med, 320 Yueyang Rd, Shanghai 200031, Peoples R China

[2] Chinese Acad Sci, 320 Yueyang Rd, Shanghai 200031, Peoples R China

[3] Univ Chinese Acad Sci, Chinese Acad Sci, Shanghai Inst Nutr & Hlth, CAS Key Lab Nutr Metab & Food Safety, 320 Yueyang Rd, Shanghai 200031, Peoples R China

[4] Fudan Univ, Shanghai Canc Ctr, Dept Colorectal Surg, Shanghai 200032, Peoples R China

[5] Fudan Univ, Shanghai Med Coll, Dept Oncol, Shanghai 200032, Peoples R China

[6] Army Med Univ, Daping Hosp, Inst Surg Res, Dept Urol, Chongqing 400042, Peoples R China

[7] Sichuan Univ, Key Lab Birth Defects & Related Dis Women & Child, Dept Obstet Gynecol & Pediat, Dept Obstet Gynecol & Pediat,Minist Educ, 20 Renmin South Rd, Chengdu 610041, Peoples R China

[8] Chinese Acad Sci, Shanghai Inst Mat Med, State Key Lab Drug Res, Shanghai 201203, Peoples R China

来源：

MOLECULAR CELL | 2021年 / 81卷 / 13期

基金：

中国国家自然科学基金;

关键词：

SET ENRICHMENT ANALYSIS; STEM-CELLS; WEB SERVER; TRANSCRIPTION; SREBP; PROTEIN; EXPRESSION; INTERPLAY; ZMYND8; TAZ;

D O I：

10.1016/j.molcel.2021.04.009

中图分类号：

Q5 [生物化学]; Q7 [分子生物学];

学科分类号：

071010 ; 081704 ;

摘要：

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.

引用

页码：2736 / +

页数：25

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