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

T. Bruno, M. Valerio, L. Casadei, F. De Nicola, F. Goeman, M. Pallocca, V. Catena, S. Iezzi, C. Sorino, A. Desantis, C. Manetti, G. Blandino, A. Floridi, M. Fanciulli

Research output: Contribution to journalArticle

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-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.
Original languageEnglish
Pages (from-to)32
Number of pages1
JournalJournal of Experimental and Clinical Cancer Research
Volume36
Issue number1
DOIs
Publication statusPublished - Feb 18 2017

Keywords

  • Che-1/AATF
  • HIF-1alpha
  • Hypoxia
  • Metabolism
  • PHD3/EGLN3
  • SIAH-2

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    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]