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

Estrogen receptor alpha (ER alpha) has a pivotal role in breast carcinogenesis by associating with various cellular factors. Selective expression of additional sex comb-like 2 (ASXL2) in ER alpha-positive breast cancer cells prompted us to investigate its role in chromatin modification required for ERa activation and breast carcinogenesis. Here, we observed that ASXL2 interacts with ligand E2-bound ERa and mediates ERa activation. Chromatin immunoprecipitation-sequencing analysis supports a positive role of ASXL2 at ERa 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 ERa 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 ERa-positive patients, we propose that ASXL2 could be a novel prognostic marker in breast cancer.