Chromatin loading of E2F-MLL complex by cancer-associated coregulator ANCCA via reading a specific histone mark.
Histone modifications are regarded as the carrier of epigenetic memory through cell divisions. How the marks facilitate cell cycle-dependent gene expression is poorly understood. The evolutionarily conserved AAA ATPase ANCCA (AAA nuclear coregulator cancer-associated protein)/ATAD2 was identified as a direct target of oncogene AIB1/ACTR/SRC-3 and a transcriptional coregulator for estrogen and androgen receptors and is strongly implicated in tumorigenesis. We report here that ANCCA directly interacts with E2F1 to E2F3 and that its N terminus interacts with both the N and C termini of E2F1. ANCCA preferentially associates via its bromodomain with H3 acetylated at lysine 14 (H3K14ac) and is required for key cell cycle gene expression and cancer cell proliferation. ANCCA associates with chromosomes at late mitosis, and its occupancy at E2F targets peaks at the G(1)-to-S transition. Strikingly, ANCCA is required for recruitment of specific E2Fs to their targets and chromatin assembly of the host cell factor 1 (HCF-1)-MLL histone methyltransferase complex. ANCCA depletion results in a marked decrease of the gene activation-linked H3K4me3 mark. Bromodomain mutations disable ANCCA function as an E2F coactivator and its ability to promote cancer cell proliferation, while ANCCA overexpression in tumors correlates with tumor growth. Together, these results suggest that ANCCA acts as a pioneer factor in E2F-dependent gene activation and that a novel mechanism involving ANCCA bromodomain may contribute to cancer cell proliferation.
Revenko
Alexey S
AS
Department of Biochemistry and Molecular Medicine, School of Medicine, University of California at Davis, Sacramento, CA 95817, USA.
Kalashnikova
Ekaterina V
EV
Gemo
Abigael T
AT
Zou
June X
JX
Chen
Hong-Wu
HW
D000074183:ATPases Associated with Diverse Cellular Activities; D000251:Adenosine Triphosphatases / Q000235:genetics* / Q000378:metabolism; D000595:Amino Acid Sequence; D000818:Animals; D002453:Cell Cycle / Q000235:genetics; D045744:Cell Line, Tumor; D049109:Cell Proliferation; D002843:Chromatin / Q000378:metabolism*; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism*; D050684:E2F Transcription Factors / Q000235:genetics / Q000378:metabolism*; D044127:Epigenesis, Genetic; D017930:Genes, Reporter; D011495:Histone-Lysine N-Methyltransferase; D006657:Histones / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D008239:Lysine / Q000378:metabolism; D008969:Molecular Sequence Data; D051788:Myeloid-Lymphoid Leukemia Protein / Q000235:genetics / Q000378:metabolism*; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D009369:Neoplasms / Q000235:genetics* / Q000503:physiopathology; D020033:Protein Isoforms / Q000235:genetics / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000235:genetics / Q000378:metabolism; D016415:Sequence Alignment; D015533:Transcriptional Activation
D002843:Chromatin; D004268:DNA-Binding Proteins; D050684:E2F Transcription Factors; D006657:Histones; C497422:KMT2A protein, human; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D020033:Protein Isoforms; D034741:RNA, Small Interfering; D051788:Myeloid-Lymphoid Leukemia Protein; D011495:Histone-Lysine N-Methyltransferase; D000251:Adenosine Triphosphatases; C544857:ATAD2 protein, human; D000074183:ATPases Associated with Diverse Cellular Activities; D008239:Lysine