Article ID | Journal | Published Year | Pages | File Type |
---|---|---|---|---|
8300459 | Biochimica et Biophysica Acta (BBA) - Gene Regulatory Mechanisms | 2015 | 36 Pages |
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.
Keywords
VHLPOZ-ZFKBSMethyl-CpG binding domainPDK-1RMAPDH5-Aza-dCHRECoCl2MBDGSEACBPFDRHIF-1TCA5-Aza-2′-deoxycytidineVon Hippel–Lindautricarboxylic acidGene Set Enrichment Analysisanalysis of varianceANOVASrahypoxia inducible factor-1Transcription factorhypoxia response elementDNA methylationTranscription regulationfalse discovery rateHypoxiaCREB binding proteinpyruvate dehydrogenaseKaisoCobalt chloride
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Authors
Christina C. Pierre, Joseph Longo, Blessing I. Bassey-Archibong, Robin M. Hallett, Snezana Milosavljevic, Laura Beatty, John A. Hassell, Juliet M. Daniel,