title: Methylation-dependent regulation of hypoxia inducible factor-1 alpha gene expression by the transcription factor Kaiso.
abstract: Low oxygen tension (hypoxia) is a common characteristic of solid tumors and strongly correlates with poor prognosis and resistance to treatment. In response to hypoxia, cells initiate a cascade of transcriptional events regulated by the hypoxia inducible factor-1 (HIF-1) heterodimer. Since the oxygen-sensitive HIF-1α subunit is stabilized during hypoxia, it functions as the regulatory subunit of the protein. To date, while the mechanisms governing HIF-1α protein stabilization and function have been well studied, those governing HIF1A gene expression are not fully understood. However, recent studies have suggested that methylation of a HIF-1 binding site in the HIF1A promoter prevents its autoregulation. Here we report that the POZ-ZF transcription factor Kaiso modulates HIF1A gene expression by binding to the methylated HIF1A promoter in a region proximal to the autoregulatory HIF-1 binding site. Interestingly, Kaiso's regulation of HIF1A occurs primarily during hypoxia, which is consistent with the finding that Kaiso protein levels peak after 4 h of hypoxic incubation and return to normoxic levels after 24 h. Our data thus support a role for Kaiso in fine-tuning HIF1A gene expression after extended periods of hypoxia.
authors.affiliation: Department of Biology, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: Christina C
authors.initials: CC
authors.lastname: Pierre
authors.affiliation: Department of Biology, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: Joseph
authors.initials: J
authors.lastname: Longo
authors.affiliation: Department of Biology, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: Blessing I
authors.initials: BI
authors.lastname: Bassey-Archibong
authors.affiliation: Department of Biochemistry & Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: Robin M
authors.initials: RM
authors.lastname: Hallett
authors.affiliation: Department of Biology, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: Snezana
authors.initials: S
authors.lastname: Milosavljevic
authors.affiliation: Department of Biology, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: Laura
authors.initials: L
authors.lastname: Beatty
authors.affiliation: Department of Biochemistry & Biomedical Sciences, McMaster University, Hamilton, ON L8S 4K1, Canada.
authors.forename: John A
authors.initials: JA
authors.lastname: Hassell
authors.affiliation: Department of Biology, McMaster University, Hamilton, ON L8S 4K1, Canada. Electronic address: danielj@mcmaster.ca.
authors.forename: Juliet M
authors.initials: JM
authors.lastname: Daniel
mesh_terms: D001943:Breast Neoplasms / Q000235:genetics; D015687:Cell Hypoxia / Q000235:genetics; D003110:Colonic Neoplasms / Q000235:genetics; D019175:DNA Methylation; D066264:Datasets as Topic / Q000706:statistics & numerical data; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D045325:HCT116 Cells; D006801:Humans; D051795:Hypoxia-Inducible Factor 1, alpha Subunit / Q000096:biosynthesis* / Q000235:genetics; D009363:Neoplasm Proteins / Q000096:biosynthesis / Q000235:genetics / Q000502:physiology*; D011401:Promoter Regions, Genetic / Q000235:genetics; D015398:Signal Transduction; D014157:Transcription Factors / Q000502:physiology*; D014158:Transcription, Genetic
chemical_list: C497442:HIF1A protein, human; D051795:Hypoxia-Inducible Factor 1, alpha Subunit; D009363:Neoplasm Proteins; D014157:Transcription Factors; C492254:ZBTB33 protein, human
keywords: DNA methylation; HIF-1; Hypoxia; Kaiso; POZ-ZF; Transcription factor; Transcription regulation