title: H3K9me3 facilitates hypoxia-induced p53-dependent apoptosis through repression of APAK.
abstract: Regions of hypoxia occur in most solid tumors, and they are associated with a poor prognostic outcome. Despite the absence of detectable DNA damage, severe hypoxia (<0.1% O2) induces a DNA damage response, including the activation of p53 and subsequent induction of p53-dependent apoptosis. Factors affecting hypoxia-induced p53-dependent apoptosis are unclear. Here we asked whether H3K9me3, through mediating gene repression, could regulate hypoxia-induced p53-dependent apoptosis. Under hypoxic conditions, increases in H3K9me3 occur in an oxygen-dependent but HIF-1-independent manner. We demonstrate that under hypoxic conditions, which induce p53 activity, the negative regulator of p53, APAK, is repressed by increases in H3K9me3 along the APAK loci. APAK repression in hypoxia is mediated by the methyltransferase SETDB1 but not Suv39h1 or G9a. Interestingly, increasing hypoxia-induced H3K9me3 through pharmacological inhibition of JMJD2 family members leads to an increase in apoptosis and decreased clonogenic survival and again correlates with APAK expression. The relevance of understanding the mechanisms of APAK expression regulation to human disease was suggested by analysis of patients with colorectal cancer, which demonstrates that high APAK expression correlates with poor prognosis. Together, these data demonstrate the functional importance of H3K9me3 in hypoxia, and they provide a novel mechanistic link between H3K9me3, p53 and apoptosis in physiologically relevant conditions of hypoxia.
authors.affiliation: Department of Oncology, CR-UK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: M M
authors.initials: MM
authors.lastname: Olcina
authors.affiliation: Department of Oncology, CR-UK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: K B
authors.initials: KB
authors.lastname: Leszczynska
authors.affiliation: Department of Oncology, CR-UK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: J M
authors.initials: JM
authors.lastname: Senra
authors.affiliation: Department of Oncology, CR-UK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: N F
authors.initials: NF
authors.lastname: Isa
authors.affiliation: Department of Radiation Oncology and Image-Applied Therapy, Kyoto University Graduate School of Medicine, Kyoto, Japan.
authors.forename: H
authors.initials: H
authors.lastname: Harada
authors.affiliation: Department of Oncology, CR-UK & MRC Oxford Institute for Radiation Oncology, University of Oxford, Oxford, UK.
authors.forename: E M
authors.initials: EM
authors.lastname: Hammond
mesh_terms: D017209:Apoptosis / Q000187:drug effects / Q000235:genetics*; D051017:Apoptosis Regulatory Proteins / Q000235:genetics* / Q000378:metabolism; D015687:Cell Hypoxia / Q000235:genetics; D004268:DNA-Binding Proteins / Q000235:genetics* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D055785:Gene Knockdown Techniques; D045325:HCT116 Cells; D011495:Histone-Lysine N-Methyltransferase / Q000378:metabolism*; D006657:Histones / Q000378:metabolism* / Q000502:physiology*; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000235:genetics; D010100:Oxygen / Q000494:pharmacology; D014407:Tumor Cells, Cultured; D016159:Tumor Suppressor Protein p53 / Q000502:physiology*
chemical_list: D051017:Apoptosis Regulatory Proteins; D004268:DNA-Binding Proteins; C497442:HIF1A protein, human; D006657:Histones; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C540923:ZNF420 protein, human; D011495:Histone-Lysine N-Methyltransferase; D010100:Oxygen