title: The atypical histone macroH2A1.2 interacts with HER-2 protein in cancer cells.
abstract: 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.
authors.affiliation: Department of Medicine, John A. Burns School of Medicine, University of Hawaii, Honolulu, Hawaii 96813, USA.
authors.forename: Xiufen
authors.initials: X
authors.lastname: Li
authors.forename: Jinqiu
authors.initials: J
authors.lastname: Kuang
authors.forename: Yi
authors.initials: Y
authors.lastname: Shen
authors.forename: Martin M
authors.initials: MM
authors.lastname: Majer
authors.forename: Chad C
authors.initials: CC
authors.lastname: Nelson
authors.forename: Krishna
authors.initials: K
authors.lastname: Parsawar
authors.forename: Karen A
authors.initials: KA
authors.lastname: Heichman
authors.forename: Scott K
authors.initials: SK
authors.lastname: Kuwada
mesh_terms: D000818:Animals; D001943:Breast Neoplasms / Q000378:metabolism; D018938:Caco-2 Cells; D002455:Cell Division / Q000502:physiology; D002467:Cell Nucleus / Q000378:metabolism; D003110:Colonic Neoplasms / Q000378:metabolism; D005260:Female; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology*; D057809:HEK293 Cells; D006657:Histones / Q000737:chemistry / Q000235:genetics / Q000378:metabolism; D006801:Humans; D051379:Mice; D008819:Mice, Nude; D009368:Neoplasm Transplantation; D009369:Neoplasms / Q000235:genetics* / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000378:metabolism; D011401:Promoter Regions, Genetic / Q000502:physiology; D054730:Protein Interaction Domains and Motifs / Q000502:physiology; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000737:chemistry / Q000235:genetics / Q000378:metabolism
chemical_list: D006657:Histones; D018719:Erb-b2 Receptor Tyrosine Kinases; C120756:macroH2A histone; C508053:ERBB2 protein, human