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-1alpha 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-1alpha 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-1alpha stability.
|Number of pages||1|
|Journal||Journal of Experimental and Clinical Cancer Research|
|Publication status||Published - Feb 18 2017|
Bruno, T., Valerio, M., Casadei, L., Nicola, F. D., Goeman, F., Pallocca, M., Catena, V., Iezzi, S., Sorino, C., Desantis, A., Manetti, C., Blandino, G., Floridi, A., & Fanciulli, M. (2017). Che-1 sustains hypoxic response of colorectal cancer cells by affecting Hif-1alpha stabilization. Journal of Experimental and Clinical Cancer Research, 36(1), 32. https://doi.org/10.1186/s13046-017-0497-1 [doi]