Che-1 sustains hypoxic response of colorectal cancer cells by affecting Hif-1α stabilization

Background: solid tumours are less oxygenated than normal tissues. consequently,cancer cells acquire to be adapted to a hypoxic environment. the poor oxygenation of solid tumours is also a major indicator of an adverse cancer prognosis and leads to resistance to conventional anticancer treatments. we previously showed the involvement of che-1/aatf (che-1) in cancer cell survival under stress conditions. herein we hypothesized that che-1 plays a role in the response of cancer cells to hypoxia. methods: the human colon adenocarcinoma hct116 and ht29 cell lines undepleted or depleted for che-1 expression by sirna,were treated under normoxic and hypoxic conditions to perform studies regarding the role of this protein in metabolic adaptation and cell proliferation. che-1 expression was detected using western blot assays; cell metabolism was assessed by nmr spectroscopy and functional assays. additional molecular studies were performed by rna seq,qrt-pcr and chip analyses. results: here we report that che-1 expression is required for the adaptation of cells to hypoxia,playing an important role in metabolic modulation. indeed,che-1 depletion impacted on hif-1α stabilization,thus downregulating the expression of several genes involved in the response to hypoxia and affecting glucose metabolism. conclusions: we show that che-1 a novel player in the regulation of hif-1α in response to hypoxia. notably,we found that che-1 is required for siah-2 expression,a member of e3 ubiquitin ligase family that is involved in the degradation of the hydroxylase phd3,the master regulator of hif-1α stability. © 2017 the author(s).