ASXL2 promotes proliferation of breast cancer cells by linking ERα to histone methylation

• Published in: Oncogene Vol. 35; no. 28; pp. 3742 - 3752
• Main Authors: Park, U-H, Kang, M-R, Kim, E-J, Kwon, Y-S, Hur, W, Yoon, S K, Song, B-J, Park, J H, Hwang, J-T, Jeong, J-C, Um, S-J
• Format: Journal Article
• Language: English
• Published: London Nature Publishing Group UK 14.07.2016; Nature Publishing Group
• Subjects: 38; 38/39; 38/61; 631/337/176; 631/45; 64; 64/60; 96/95; Animals; Apoptosis; Biomarkers, Tumor - genetics; Biomarkers, Tumor - metabolism; Blotting, Western; Breast cancer; Breast Neoplasms - genetics; Breast Neoplasms - metabolism; Breast Neoplasms - pathology; Carcinogenesis; Care and treatment; Cell Biology; Cell Proliferation; Cell size; Cellular proteins; Chromatin; Development and progression; DNA methylation; DNA-Binding Proteins - metabolism; Estrogen Receptor alpha - metabolism; Estrogen receptors; Female; Gene expression; Gene Expression Profiling; Gene Expression Regulation, Neoplastic; Genetic aspects; Health aspects; HEK293 Cells; Histone Demethylases - metabolism; Histone H3; Histones; Histones - metabolism; Human Genetics; Humans; Immunoprecipitation; Internal Medicine; Lysine; Lysine - metabolism; MCF-7 Cells; Medicine; Medicine & Public Health; Methylation; Mice, Inbred BALB C; Mice, Nude; Neoplasm Proteins - metabolism; Oncology; original-article; Prognosis; Properties; Protein Binding; Repressor Proteins - genetics; Repressor Proteins - metabolism; Reverse Transcriptase Polymerase Chain Reaction; Sequence analysis; Transplantation, Heterologous; Xenografts
• ISSN: 0950-9232; 1476-5594
• DOI: 10.1038/onc.2015.443

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.