2. Academic Validation
  3. ZMYND8 is a master regulator of 27-hydroxycholesterol that promotes tumorigenicity of breast cancer stem cells

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

  • Sci Adv. 2022 Jul 15;8(28):eabn5295. doi: 10.1126/sciadv.abn5295.
Maowu Luo 1,  Lei Bao 1,  Yan Chen 1,  Yuanyuan Xue 2,  Yong Wang 1,  Bo Zhang 1,  Chenliang Wang 1,  Chase D Corley 3,  Jeffrey G McDonald 3 4,  Ashwani Kumar 5,  Chao Xing 5 6 7,  Yisheng Fang 1,  Erik R Nelson 8 9 10,  Jennifer E Wang 1,  Yingfei Wang 1 11 12,  Weibo Luo 1 13
Affiliations

Affiliations

  • 1 Department of Pathology, UT Southwestern Medical Center, Dallas, TX, USA.
  • 2 Children's Medical Center Research Institute, UT Southwestern Medical Center, Dallas, TX, USA.
  • 3 Center for Human Nutrition, UT Southwestern Medical Center, Dallas, TX, USA.
  • 4 Department of Molecular Genetics, UT Southwestern Medical Center, Dallas, TX, USA.
  • 5 Eugene McDermott Center for Human Growth and Development, UT Southwestern Medical Center, Dallas, TX, USA.
  • 6 Lyda Hill Department of Bioinformatics, UT Southwestern Medical Center, Dallas, TX, USA.
  • 7 Department of Population and Data Sciences, UT Southwestern Medical Center, Dallas, TX, USA.
  • 8 Department of Molecular and Integrative Physiology, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • 9 Cancer Center at Illinois, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • 10 Carl R. Woese Institute for Genomic Biology, University of Illinois Urbana-Champaign, Urbana, IL, USA.
  • 11 Department of Neurology, UT Southwestern Medical Center, Dallas, TX, USA.
  • 12 Peter O'Donnell Jr. Brain Institute, UT Southwestern Medical Center, Dallas, TX, USA.
  • 13 Department of Pharmacology, UT Southwestern Medical Center, Dallas, TX, USA.
PMID: 35857506 DOI: 10.1126/sciadv.abn5295
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.

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