ASXL2 promotes proliferation of breast cancer cells by linking ER[alpha] to histone methylation

Estrogen receptor alpha (ER) has a pivotal role in breast carcinogenesis by associating with various cellular factors. Selective expression of additional sex comb-like 2 (ASXL2) in ER-positive breast cancer cells prompted us to investigate its role in chromatin modication required for ER activation and breast carcinogenesis. Here, we observed that ASXL2 interacts with ligand E2-bound ER and mediates ER activation. Chromatin immunoprecipitation-sequencing analysis supports a positive role of ASXL2 at ER target gene promoters. ASXL2 forms a complex with histone methylation modiers 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 nger of ASXL2 to the dimethylated H3 lysine 4 may account for its requirement for ER 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 ER-positive patients, we propose that ASXL2 could be a novel prognostic marker in breast cancer.