title: ASXL2 promotes proliferation of breast cancer cells by linking ERα to histone methylation.
abstract: Estrogen receptor alpha (ERα) has a pivotal role in breast carcinogenesis by associating with various cellular factors. Selective expression of additional sex comb-like 2 (ASXL2) in ERα-positive breast cancer cells prompted us to investigate its role in chromatin modification required for ERα activation and breast carcinogenesis. Here, we observed that ASXL2 interacts with ligand E2-bound ERα and mediates ERα activation. Chromatin immunoprecipitation-sequencing analysis supports a positive role of ASXL2 at ERα target gene promoters. ASXL2 forms a complex with histone methylation modifiers including LSD1, UTX and MLL2, which all are recruited to the E2-responsive genes via ASXL2 and regulate methylations at histone H3 lysine 4, 9 and 27. The preferential binding of the PHD finger of ASXL2 to the dimethylated H3 lysine 4 may account for its requirement for ERα activation. On ASXL2 depletion, the proliferative potential of MCF7 cells and tumor size of xenograft mice decreased. Together with our finding on the higher ASXL2 expression in ERα-positive patients, we propose that ASXL2 could be a novel prognostic marker in breast cancer.
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea.
authors.forename: U-H
authors.initials: UH
authors.lastname: Park
authors.affiliation: Bioevaluation Center, Korea Research Institute of Bioscience and Biotechnology, Ochang, Cheongwon, Korea.
authors.forename: M-R
authors.initials: MR
authors.lastname: Kang
authors.affiliation: Department of Molecular Biology, Dankook University, Gyeonggi-do, Korea.
authors.forename: E-J
authors.initials: EJ
authors.lastname: Kim
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea.
authors.forename: Y-S
authors.initials: YS
authors.lastname: Kwon
authors.affiliation: The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, The Catholic University, College of Medicine, Seoul, Korea.
authors.forename: W
authors.initials: W
authors.lastname: Hur
authors.affiliation: The Catholic University Liver Research Center and WHO Collaborating Center of Viral Hepatitis, The Catholic University, College of Medicine, Seoul, Korea.
authors.forename: S K
authors.initials: SK
authors.lastname: Yoon
authors.affiliation: Breast Center Departments of Surgery, Seoul St. Mary's Hospital College of Medicine, The Catholic University, Seoul, Korea.
authors.forename: B-J
authors.initials: BJ
authors.lastname: Song
authors.affiliation: Korea Food Research Institute, Bundang-gu, Korea.
authors.forename: J H
authors.initials: JH
authors.lastname: Park
authors.affiliation: Korea Food Research Institute, Bundang-gu, Korea.
authors.forename: J-T
authors.initials: JT
authors.lastname: Hwang
authors.affiliation: Department of Biochemistry, Molecular Biology and Internal Medicine, College of Oriental Medicine, Dongguk University, Kyungpook, Korea.
authors.forename: J-C
authors.initials: JC
authors.lastname: Jeong
authors.affiliation: Department of Bioscience and Biotechnology, Sejong University, Seoul, Korea.
authors.forename: S-J
authors.initials: SJ
authors.lastname: Um
mesh_terms: D000818:Animals; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D015153:Blotting, Western; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism* / Q000473:pathology; D049109:Cell Proliferation; D004268:DNA-Binding Proteins / Q000378:metabolism; D047628:Estrogen Receptor alpha / Q000378:metabolism*; D005260:Female; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D057809:HEK293 Cells; D056466:Histone Demethylases / Q000378:metabolism; D006657:Histones / Q000378:metabolism*; D006801:Humans; D008239:Lysine / Q000378:metabolism; D061986:MCF-7 Cells; D008745:Methylation; D008807:Mice, Inbred BALB C; D008819:Mice, Nude; D009363:Neoplasm Proteins / Q000378:metabolism; D011379:Prognosis; D011485:Protein Binding; D012097:Repressor Proteins / Q000235:genetics / Q000378:metabolism*; D020133:Reverse Transcriptase Polymerase Chain Reaction; D014183:Transplantation, Heterologous
chemical_list: C484295:ASXL2 protein, human; D014408:Biomarkers, Tumor; D004268:DNA-Binding Proteins; D047628:Estrogen Receptor alpha; D006657:Histones; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D012097:Repressor Proteins; D056466:Histone Demethylases; C495195:KDM1A protein, human; D008239:Lysine