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

J Exp Clin Cancer Res. 2017 Feb 18;36(1):32. doi: 10.1186/s13046-017-0497-1.

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.

Keywords: Che-1/AATF; HIF-1α; Hypoxia; Metabolism; PHD3/EGLN3; SIAH-2.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Apoptosis Regulatory Proteins / genetics*
  • Cell Hypoxia
  • Cell Proliferation
  • Colorectal Neoplasms / chemistry
  • Colorectal Neoplasms / genetics*
  • Gene Expression Regulation, Neoplastic
  • Glucose / metabolism
  • HCT116 Cells
  • HT29 Cells
  • Humans
  • Hypoxia-Inducible Factor 1, alpha Subunit / chemistry*
  • Hypoxia-Inducible Factor 1, alpha Subunit / genetics*
  • Protein Stability
  • Repressor Proteins / genetics*
  • Sequence Analysis, RNA

Substances

  • AATF protein, human
  • Apoptosis Regulatory Proteins
  • HIF1A protein, human
  • Hypoxia-Inducible Factor 1, alpha Subunit
  • Repressor Proteins
  • Glucose