title: Identification of MYST3 as a novel epigenetic activator of ERα frequently amplified in breast cancer.
abstract: Estrogen receptor α (ERα) is a master driver of a vast majority of breast cancers. Breast cancer cells often develop resistance to endocrine therapy via restoration of the ERα activity through survival pathways. Thus identifying the epigenetic activator of ERα that can be targeted to block ERα gene expression is a critical topic of endocrine therapy. Here, integrative genomic analysis identified MYST3 as a potential oncogene target that is frequently amplified in breast cancer. MYST3 is involved in histone acetylation via its histone acetyltransferase domain (HAT) and, as a result, activates gene expression by altering chromatin structure. We found that MYST3 was amplified in 11% and/or overexpressed in 15% of breast tumors, and overexpression of MYST3 correlated with worse clinical outcome in estrogen receptor+ (ER+) breast cancers. Interestingly, MYST3 depletion drastically inhibited proliferation in MYST3-high, ER+ breast cancer cells, but not in benign breast epithelial cells or in MYST3-low breast cancer cells. Importantly, we discovered that knocking down MYST3 resulted in profound reduction of ERα expression, while ectopic expression of MYST3 had the reversed effect. Chromatin immunoprecipitation revealed that MYST3 binds to the proximal promoter region of ERα gene, and inactivating mutations in its HAT domain abolished its ability to regulate ERα, suggesting MYST3 functioning as a histone acetyltransferase that activates ERα promoter. Furthermore, MYST3 inhibition with inducible MYST3 shRNAs potently attenuated breast tumor growth in mice. Together, this study identifies the first histone acetyltransferase that activates ERα expression which may be potentially targeted to block ERα at transcriptional level.
authors.affiliation: The Michael E. DeBakey, Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
authors.forename: L
authors.initials: L
authors.lastname: Yu
authors.affiliation: The Michael E. DeBakey, Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
authors.forename: Y
authors.initials: Y
authors.lastname: Liang
authors.affiliation: Lester &Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.|Department of Medicine, Baylor College of Medicine, Houston, TX, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.
authors.forename: X
authors.initials: X
authors.lastname: Cao
authors.affiliation: Lester &Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.|Department of Medicine, Baylor College of Medicine, Houston, TX, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.|University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: X
authors.initials: X
authors.lastname: Wang
authors.affiliation: The Michael E. DeBakey, Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
authors.forename: H
authors.initials: H
authors.lastname: Gao
authors.affiliation: Department of Systems Biology, University of Texas, MD Anderson Cancer Center, Houston, TX, USA.
authors.forename: S-Y
authors.initials: SY
authors.lastname: Lin
authors.affiliation: Lester &Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.|Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
authors.forename: R
authors.initials: R
authors.lastname: Schiff
authors.affiliation: Lester &Sue Smith Breast Center, Baylor College of Medicine, Houston, TX, USA.|Dan L. Duncan Cancer Center, Baylor College of Medicine, Houston, TX, USA.|Department of Medicine, Baylor College of Medicine, Houston, TX, USA.|Department of Molecular and Cellular Biology, Baylor College of Medicine, Houston, TX, USA.|University of Pittsburgh Cancer Institute, University of Pittsburgh, Pittsburgh, PA, USA.|Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
authors.forename: X-S
authors.initials: XS
authors.lastname: Wang
authors.affiliation: The Michael E. DeBakey, Department of Surgery, Baylor College of Medicine, Houston, TX, USA.
authors.forename: K
authors.initials: K
authors.lastname: Li
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism*; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D004195:Disease Models, Animal; D044127:Epigenesis, Genetic; D047628:Estrogen Receptor alpha / Q000235:genetics* / Q000378:metabolism*; D005260:Female; D005784:Gene Amplification; D015972:Gene Expression Regulation, Neoplastic; D055785:Gene Knockdown Techniques; D051548:Histone Acetyltransferases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D023041:Xenograft Model Antitumor Assays
chemical_list: D047628:Estrogen Receptor alpha; D051548:Histone Acetyltransferases; C108712:KAT6A protein, human