Che-1 sustains hypoxic response of colorectal cancer cells by affecting Hif-1\u03b1 stabilization

Tiziana Bruno,Matteo Pallocca,Cristina Sorino,Luca Casadei,Mariacristina Valerio,Maurizio Fanciulli,Francesca De Nicola,Aristide Floridi,Simona Iezzi,Frauke Goeman,Agata Desantis,Valeria Catena,Giovanni Blandino,Cesare Manetti

doi:10.1186/s13046-017-0497-1

Tiziana Bruno, Matteo Pallocca + Show 12 more

Open Access

https://doi.org/10.1186/s13046-017-0497-1

Copy DOI

Abstract

BackgroundSolid 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.MethodsThe 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.ResultsHere 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.ConclusionsWe 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.

Highlights

Solid tumours are less oxygenated than normal tissues
Che-1 protects colon cancer cells from apoptosis induced by hypoxia Over the last few years, Che-1 has been identified as a protein involved in several cellular pathways including the control of transcription and apoptosis [14]
Several findings indicate that Che-1 is involved in DNA damage response (DDR) and in other types of stress

Summary

Introduction

Solid tumours are less oxygenated than normal tissues. The poor oxygenation of solid tumours is a major indicator of an adverse cancer prognosis and leads to resistance to conventional anticancer treatments. I.e. low levels of O2, is a common feature of solid tumours, which leads to an aggressive tumor phenotype. Hypoxia is associated with resistance to therapeutic treatments and with a poor clinical prognosis [1]. The main adaptation of tumor cell to hypoxia is the switch from an aerobic metabolism to glycolysis [2]. Glycolysis provides precursors for the synthesis of nucleic acids, lipids and amino acids that are crucial to enhance survival and growth of cancer cells both during carcinogenesis, and in metastatic tumours [4, 5]. In low oxygen tension HIF-1α is quickly stabilized and affects most of

Methods

Results

Conclusion