Che-1 sustains hypoxic response of colorectal cancer cells by affecting Hif-1α stabilization. Issue 1 (December 2017)

• Record Type: Journal Article
• Authors: Bruno, Tiziana; Valerio, Mariacristina; Casadei, Luca; De Nicola, Francesca; Goeman, Frauke; Pallocca, Matteo; Catena, Valeria; Iezzi, Simona; Sorino, Cristina; Desantis, Agata; Manetti, Cesare; Blandino, Giovanni; Floridi, Aristide; Fanciulli, Maurizio
• Is Part Of: Journal of experimental & clinical cancer research. Volume 36:Issue 1(2017)
• Page Start: 1
• Page End: 11
• Publication Date: 2017-12
• Subjects: Che-1/AATF -- Hypoxia -- Metabolism -- HIF-1α -- PHD3/EGLN3 -- SIAH-2; Cancer -- Periodicals; 616.994005
• DOI: 10.1186/s13046-017-0497-1
• Languages: English
• ISSNs: 1756-9966

Abstract

Abstract 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.