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 HIF1α in HNSCC cells. It inhibits HIF1α 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 HIF1Α 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 HIF1Α mRNA and the hypoxia-response genes.
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We thank members of PR and SB Laboratory for helpful guidance during this study. We especially thank Caius Coretchi for his technical assistance as summer research student in the College of Dentistry.
This work was supported by the grants from National Cancer Institute (NCI) to SB (R03CA227308) and the multi-PI grant from the National Cancer Institute (NCI) to PR and SB (R01CA156164).
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The authors declare that they have no conflict of interest.
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Bommi, P.V., Chand, V., Mukhopadhyay, N.K. et al. NER-factor DDB2 regulates HIF1α and hypoxia-response genes in HNSCC. Oncogene 39, 1784–1796 (2020). https://doi.org/10.1038/s41388-019-1105-y