The Atypical Histone MacroH2A1.2 Interacts with HER-2 Protein in Cancer Cells

Because HER-2 has been demonstrated in the nuclei of cancer cells, we hypothesized that it might interact with transcription factors that activate ERBB2 transcription. Macrohistone 2A1 ( H2AFY; mH2A1) was found to interact with HER-2 in cancer cells that overexpress HER-2. Of the two human mH2A1 isoforms, mH2A1.2, but not mH2A1.1, interacted with HER-2 in human cancer cell lines. Overexpression of mH2A1.2, but not mH2A1.1, in cancer cells significantly increased HER-2 expression and tumorigenicity. Inhibition of HER-2 kinase activity diminished mH2A1 expression and mH2A1.2-induced ERBB2 transcription in cancer cells. Chromatin immunoprecipitation of mH2A1.2 in cancer cells stably transfected with mH2A1.2 showed enrichment of mH2A1.2 at the HER-2 promoter, suggesting a role for mH2A1.2 in driving HER-2 overexpression. The evolutionarily conserved macro domain of mH2A1.2 was sufficient for the interaction between HER-2 and mH2A1.2 and for mH2A1.2-induced ERBB2 transcription. Within the macro domain of mH2A1.2, a trinucleotide insertion (-EIS-) sequence not found in mH2A1.1 was essential for the interaction between HER-2 and mH2A1.2 as well as mH2A1.2-induced HER-2 expression and cell proliferation.