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

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^*

^*Corresponding author for this work

Research output: Journal Publications and Reviews › RGC 21 - Publication in refereed journal › peer-review

49 Citations (Scopus)

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. © 2021 Elsevier Inc.

Original language	English
Pages (from-to)	2736-2751.e8
Journal	Molecular Cell
Volume	81
Issue number	13
Online published	30 Apr 2021
DOIs	https://doi.org/10.1016/j.molcel.2021.04.009
Publication status	Published - 1 Jul 2021
Externally published	Yes

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This output contributes to the following UN Sustainable Development Goals (SDGs)

SDG 3 Good Health and Well-being

Research Keywords

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

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Pan, Q., Zhong, S., Wang, H., Wang, X., Li, N., Li, Y., Zhang, G., Yuan, H., Lian, Y., Chen, Q., Han, Y., Guo, J., Liu, Q., Qiu, T., Jiang, J., Li, Q., Tan, M., Yin, H., Peng, J., ... Qin, J. (2021). The ZMYND8-regulated mevalonate pathway endows YAP-high intestinal cancer with metabolic vulnerability. Molecular Cell, 81(13), 2736-2751.e8. https://doi.org/10.1016/j.molcel.2021.04.009

@article{c9e31134a2834882b732ac7f0ec82cda,

title = "The ZMYND8-regulated mevalonate pathway endows YAP-high intestinal cancer with metabolic vulnerability",

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. {\textcopyright} 2021 Elsevier Inc.",

keywords = "Colorectal cancer, Enhancer-promoter contact, Intestinal stem cell (ISC), Mevalonate (MVA) pathway, YAP, ZMYND8",

author = "Qiang Pan and Shanshan Zhong and Hanling Wang and Xuege Wang and Ni Li and Yaqi Li and Guoying Zhang and Huairui Yuan and Yannan Lian and Qilong Chen and Ying Han and Jiacheng Guo and Qiuli Liu and Tong Qiu and Jun Jiang and Qintong Li and Minjia Tan and Huiyong Yin and Junjie Peng and Yichuan Xiao and Jun Qin",

year = "2021",

month = jul,

day = "1",

doi = "10.1016/j.molcel.2021.04.009",

language = "English",

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pages = "2736--2751.e8",

journal = "Molecular Cell",

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Pan, Q, Zhong, S, Wang, H, Wang, X, Li, N, Li, Y, Zhang, G, Yuan, H, Lian, Y, Chen, Q, Han, Y, Guo, J, Liu, Q, Qiu, T, Jiang, J, Li, Q, Tan, M, Yin, H, Peng, J, Xiao, Y & Qin, J 2021, 'The ZMYND8-regulated mevalonate pathway endows YAP-high intestinal cancer with metabolic vulnerability', Molecular Cell, vol. 81, no. 13, pp. 2736-2751.e8. https://doi.org/10.1016/j.molcel.2021.04.009

TY - JOUR

T1 - The ZMYND8-regulated mevalonate pathway endows YAP-high intestinal cancer with metabolic vulnerability

AU - Pan, Qiang

AU - Zhong, Shanshan

AU - Wang, Hanling

AU - Wang, Xuege

AU - Li, Ni

AU - Li, Yaqi

AU - Zhang, Guoying

AU - Yuan, Huairui

AU - Lian, Yannan

AU - Chen, Qilong

AU - Han, Ying

AU - Guo, Jiacheng

AU - Liu, Qiuli

AU - Qiu, Tong

AU - Jiang, Jun

AU - Li, Qintong

AU - Tan, Minjia

AU - Yin, Huiyong

AU - Peng, Junjie

AU - Xiao, Yichuan

AU - Qin, Jun

PY - 2021/7/1

Y1 - 2021/7/1

N2 - 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. © 2021 Elsevier Inc.

AB - 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. © 2021 Elsevier Inc.

KW - Colorectal cancer

KW - Enhancer-promoter contact

KW - Intestinal stem cell (ISC)

KW - Mevalonate (MVA) pathway

KW - YAP

KW - ZMYND8

UR - https://www.scopus.com/pages/publications/85108879975

UR - https://www.scopus.com/record/pubmetrics.uri?eid=2-s2.0-85108879975&origin=recordpage

U2 - 10.1016/j.molcel.2021.04.009

DO - 10.1016/j.molcel.2021.04.009

M3 - RGC 21 - Publication in refereed journal

C2 - 33932349

SN - 1097-2765

VL - 81

SP - 2736-2751.e8

JO - Molecular Cell

JF - Molecular Cell

IS - 13

ER -

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

Abstract

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