ZMYND8 is a master regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells

Maowu Luo; Lei Bao; Yan Chen; Yuanyuan Xue; Yong Wang; Bo Zhang; Chenliang Wang; Chase D. Corley; Jeffrey G. McDonald; Ashwani Kumar; Chao Xing; Yisheng Fang; Erik R. Nelson; Jennifer E. Wang; Yingfei Wang; Weibo Luo

doi:10.1126/sciadv.abn5295

ZMYND8 is a master regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells

Maowu Luo, Lei Bao, Yan Chen, Yuanyuan Xue, Yong Wang, Bo Zhang, Chenliang Wang, Chase D. Corley, Jeffrey G. McDonald, Ashwani Kumar, Chao Xing, Yisheng Fang, Erik R. Nelson, Jennifer E. Wang, Yingfei Wang, Weibo Luo

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Abstract

27-Hydroxycholesterol (27-HC) is the most abundant oxysterol that increases the risk of breast cancer progression. However, little is known about epigenetic regulation of 27-HC metabolism and its role in breast tumor initiation. Using genetic mouse mammary tumor and human breast cancer models, we showed here that the histone reader ZMYND8 was selectively expressed in breast cancer stem cells (BCSCs) and promoted epithelial-mesenchymal transition (EMT), BCSC maintenance and self-renewal, and oncogenic transformation through its epigenetic functions, leading to breast tumor initiation. Mechanistically, ZMYND8 was a master transcriptional regulator of 27-HC metabolism. It increased cholesterol biosynthesis and oxidation but blocked cholesterol efflux and 27-HC catabolism, leading to accumulation of 27-HC in BCSCs. Consequently, 27-HC promoted EMT, oncogenic transformation, and tumor initiation through activation of liver X receptor. These findings reveal that ZMYND8 is an epigenetic booster that drives breast tumor initiation through metabolic reprogramming.

Original language	English (US)
Article number	abn5295
Journal	Science Advances
Volume	8
Issue number	28
DOIs	https://doi.org/10.1126/sciadv.abn5295
State	Published - 2022

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Luo, M., Bao, L., Chen, Y., Xue, Y., Wang, Y., Zhang, B., Wang, C., Corley, C. D., McDonald, J. G., Kumar, A., Xing, C., Fang, Y., Nelson, E. R., Wang, J. E., Wang, Y., & Luo, W. (2022). ZMYND8 is a master regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells. Science Advances, 8(28), Article abn5295. https://doi.org/10.1126/sciadv.abn5295

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title = "ZMYND8 is a master regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells",

abstract = "27-Hydroxycholesterol (27-HC) is the most abundant oxysterol that increases the risk of breast cancer progression. However, little is known about epigenetic regulation of 27-HC metabolism and its role in breast tumor initiation. Using genetic mouse mammary tumor and human breast cancer models, we showed here that the histone reader ZMYND8 was selectively expressed in breast cancer stem cells (BCSCs) and promoted epithelial-mesenchymal transition (EMT), BCSC maintenance and self-renewal, and oncogenic transformation through its epigenetic functions, leading to breast tumor initiation. Mechanistically, ZMYND8 was a master transcriptional regulator of 27-HC metabolism. It increased cholesterol biosynthesis and oxidation but blocked cholesterol efflux and 27-HC catabolism, leading to accumulation of 27-HC in BCSCs. Consequently, 27-HC promoted EMT, oncogenic transformation, and tumor initiation through activation of liver X receptor. These findings reveal that ZMYND8 is an epigenetic booster that drives breast tumor initiation through metabolic reprogramming.",

author = "Maowu Luo and Lei Bao and Yan Chen and Yuanyuan Xue and Yong Wang and Bo Zhang and Chenliang Wang and Corley, {Chase D.} and McDonald, {Jeffrey G.} and Ashwani Kumar and Chao Xing and Yisheng Fang and Nelson, {Erik R.} and Wang, {Jennifer E.} and Yingfei Wang and Weibo Luo",

note = "Publisher Copyright: Copyright {\textcopyright} 2022 The Authors",

year = "2022",

doi = "10.1126/sciadv.abn5295",

language = "English (US)",

volume = "8",

journal = "Science Advances",

issn = "2375-2548",

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T1 - ZMYND8 is a master regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells

AU - Luo, Maowu

AU - Bao, Lei

AU - Chen, Yan

AU - Xue, Yuanyuan

AU - Wang, Yong

AU - Zhang, Bo

AU - Wang, Chenliang

AU - Corley, Chase D.

AU - McDonald, Jeffrey G.

AU - Kumar, Ashwani

AU - Xing, Chao

AU - Fang, Yisheng

AU - Nelson, Erik R.

AU - Wang, Jennifer E.

AU - Wang, Yingfei

AU - Luo, Weibo

PY - 2022

Y1 - 2022

N2 - 27-Hydroxycholesterol (27-HC) is the most abundant oxysterol that increases the risk of breast cancer progression. However, little is known about epigenetic regulation of 27-HC metabolism and its role in breast tumor initiation. Using genetic mouse mammary tumor and human breast cancer models, we showed here that the histone reader ZMYND8 was selectively expressed in breast cancer stem cells (BCSCs) and promoted epithelial-mesenchymal transition (EMT), BCSC maintenance and self-renewal, and oncogenic transformation through its epigenetic functions, leading to breast tumor initiation. Mechanistically, ZMYND8 was a master transcriptional regulator of 27-HC metabolism. It increased cholesterol biosynthesis and oxidation but blocked cholesterol efflux and 27-HC catabolism, leading to accumulation of 27-HC in BCSCs. Consequently, 27-HC promoted EMT, oncogenic transformation, and tumor initiation through activation of liver X receptor. These findings reveal that ZMYND8 is an epigenetic booster that drives breast tumor initiation through metabolic reprogramming.

AB - 27-Hydroxycholesterol (27-HC) is the most abundant oxysterol that increases the risk of breast cancer progression. However, little is known about epigenetic regulation of 27-HC metabolism and its role in breast tumor initiation. Using genetic mouse mammary tumor and human breast cancer models, we showed here that the histone reader ZMYND8 was selectively expressed in breast cancer stem cells (BCSCs) and promoted epithelial-mesenchymal transition (EMT), BCSC maintenance and self-renewal, and oncogenic transformation through its epigenetic functions, leading to breast tumor initiation. Mechanistically, ZMYND8 was a master transcriptional regulator of 27-HC metabolism. It increased cholesterol biosynthesis and oxidation but blocked cholesterol efflux and 27-HC catabolism, leading to accumulation of 27-HC in BCSCs. Consequently, 27-HC promoted EMT, oncogenic transformation, and tumor initiation through activation of liver X receptor. These findings reveal that ZMYND8 is an epigenetic booster that drives breast tumor initiation through metabolic reprogramming.

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ZMYND8 is a master regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells

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