NER-factor DDB2 regulates HIF1[alpha] and hypoxia-response genes in HNSCC

Cancers in the oral/head & neck region (HNSCC) are aggressive due to high incidence of recurrence and distant metastasis. One prominent feature of aggressive HNSCC is the presence of severely hypoxic regions in tumors and activation of hypoxia-inducible factors (HIFs). In this study, we report t...

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Veröffentlicht in:Oncogene 2020, Vol.39 (8), p.1784
Hauptverfasser: Bommi, Prashant V, Chand, Vaibhav, Mukhopadhyay, Nishit K, Raychaudhuri, Pradip, Bagchi, Srilata
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Sprache:eng
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Zusammenfassung:Cancers in the oral/head & neck region (HNSCC) are aggressive due to high incidence of recurrence and distant metastasis. One prominent feature of aggressive HNSCC is the presence of severely hypoxic regions in tumors and activation of hypoxia-inducible factors (HIFs). In this study, we report that the XPE gene product DDB2 (damaged DNA binding protein 2), a nucleotide excision repair protein, is upregulated by hypoxia. Moreover, DDB2 inhibits HIF1[alpha] in HNSCC cells. It inhibits HIF1[alpha] in both normoxia and hypoxia by reducing mRNA expression. Knockdown of DDB2 enhances the expression of angiogenic markers and promotes tumor growth in a xenograft model. We show that DDB2 binds to an upstream promoter element in the HIF1[ALPHA] gene and promotes histone H3K9 trimethylation around the binding site by recruiting Suv39h1. Also, we provide evidence that DDB2 has a significant suppressive effect on expression of the endogenous markers of hypoxia that are also prognostic indicators in HNSCC. Together, these results describe a new mechanism of hypoxia regulation that opposes expression of HIF1[ALPHA] mRNA and the hypoxia-response genes.
ISSN:0950-9232
DOI:10.1038/s41388-019-1105-y