1. Academic Validation
  2. CHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-mediated metabolism

CHCHD4 regulates tumour proliferation and EMT-related phenotypes, through respiratory chain-mediated metabolism

  • Cancer Metab. 2019 Jul 16;7:7. doi: 10.1186/s40170-019-0200-4.
Luke W Thomas 1 Cinzia Esposito 1 2 Jenna M Stephen 1 Ana S H Costa 3 Christian Frezza 3 Thomas S Blacker 4 Gyorgy Szabadkai 4 Margaret Ashcroft 1
Affiliations

Affiliations

  • 1 1Department of Medicine, University of Cambridge, Cambridge Biomedical Campus, Cambridge, CB2 0AH UK.
  • 2 4Present Address: Department of Molecular Life Sciences, University of Zurich, Winterthurerstrasse 190, CH-8057 Zurich, Switzerland.
  • 3 2Medical Research Council Cancer Unit, University of Cambridge, Hutchison/MRC Research Centre, Cambridge Biomedical Campus, Box 197, Cambridge, CB2 0XZ UK.
  • 4 3Department of Cell and Developmental Biology, Division of Biosciences, University College London, Gower Street, London, WC1E 6BT UK.
Abstract

Background: Mitochondrial Oxidative Phosphorylation (OXPHOS) via the respiratory chain is required for the maintenance of tumour cell proliferation and regulation of epithelial to mesenchymal transition (EMT)-related phenotypes through mechanisms that are not fully understood. The essential mitochondrial import protein coiled-coil helix coiled-coil helix domain-containing protein 4 (CHCHD4) controls respiratory chain complex activity and oxygen consumption, and regulates the growth of tumours in vivo. In this study, we interrogate the importance of CHCHD4-regulated Mitochondrial Metabolism for tumour cell proliferation and EMT-related phenotypes, and elucidate key pathways involved.

Results: Using in silico analyses of 967 tumour cell lines, and tumours from different Cancer patient cohorts, we show that CHCHD4 expression positively correlates with OXPHOS and proliferative pathways including the mTORC1 signalling pathway. We show that CHCHD4 expression significantly correlates with the doubling time of a range of tumour cell lines, and that CHCHD4-mediated tumour cell growth and mTORC1 signalling is coupled to respiratory chain complex I (CI) activity. Using global metabolomics analysis, we show that CHCHD4 regulates amino acid metabolism, and that CHCHD4-mediated tumour cell growth is dependent on glutamine. We show that CHCHD4-mediated tumour cell growth is linked to CI-regulated mTORC1 signalling and amino acid metabolism. Finally, we show that CHCHD4 expression in tumours is inversely correlated with EMT-related gene expression, and that increased CHCHD4 expression in tumour cells modulates EMT-related phenotypes.

Conclusions: CHCHD4 drives tumour cell growth and activates mTORC1 signalling through its control of respiratory chain mediated metabolism and complex I biology, and also regulates EMT-related phenotypes of tumour cells.

Keywords

Coiled-coil helix coiled-coil helix domain-containing protein 4 (CHCHD4); HIF-1α; complex I; disulfide relay system; hypoxia; mitochondria; respiratory chain; tumour growth; tumour metabolism.

Figures
Products