Abstract
Hypoxia, the reduction of oxygen levels in cells or tissues, elicits a set of genes to adjust physiological and pathological demands during normal development and cancer progression. Hypoxia-mediated stabilization of hypoxia-inducible factor (HIF) 1α and 2α contributes to transcriptional regulation of genes involved in hypoxia-mediated physiological adaptation. Till now, the molecular mechanism of how HIF1α and HIF2α signaling regulates cancer cell proliferation and quiescence in hypoxic microenvironment is little understood. Here, we reported that CITED2, a cytokine inducible transcriptional modulator, is induced by HIF2α to regulate cell proliferation and quiescence. We observed that HIF2α expression is induced by hypoxia in a subgroup of lung cancer cells, proliferation of which is regulated via HIF2α/CITED2 signaling. Interestingly, HIF1α-silencing promotes hypoxic-mediated cell proliferation in the HIF2α-positive lung cancer cells. In contrast, knockdown of HIF2α as well as CITED2 attenuates cell growth, suggesting that HIF2α/CITED2 signaling functions as a molecular switch for cell proliferation and quiescence. Soft-agar assay showed that HIF2α promotes anchorage-independent growth of cancer cells, which can be inhibited by CITED2-silencing. We observed that upon hypoxia induction, CITED2 enhances MYC-mediated transactivation of downstream target genes. Our findings provide a novel oncogenic role of CITED2 in hypoxia with potential as a biomarker and therapeutic targets for lung cancer.