Grainyhead-like 2 reverses the metabolic changes induced by the oncogenic epithelial-mesenchymal transition: effects on anoikis

Farris, J.C., Pifer, P. M., Zheng, L., Gottlieb, E. , Denvir, J. and Frisch, S.M. (2016) Grainyhead-like 2 reverses the metabolic changes induced by the oncogenic epithelial-mesenchymal transition: effects on anoikis. Molecular Cancer Research, 14(6), pp. 528-538. (doi: 10.1158/1541-7786.mcr-16-0050) (PMID:27084311)

Abstract

Resistance to anoikis is a prerequisite for tumor metastasis. The epithelial-to-mesenchymal transition (EMT) allows tumor cells to evade anoikis. The wound-healing regulatory transcription factor Grainyhead-like 2 (GRHL2) suppresses/reverses EMT, accompanied by suppression of the cancer stem cell (CSC) phenotype and by resensitization to anoikis. Here, the effects of GRHL2 upon intracellular metabolism in the context of reversion of the EMT/CSC phenotype, with a view toward understanding how these effects promote anoikis sensitivity, were investigated. EMT enhanced mitochondrial oxidative metabolism. Although this was accompanied by higher accumulation of superoxide, the overall level of reactive oxygen species (ROS) declined, due to decreased hydrogen peroxide. Glutamate dehydrogenase 1 (GLUD1) expression increased in EMT, and this increase, via the product α-ketoglutarate (α-KG), was important for suppressing hydrogen peroxide and protecting against anoikis. GRHL2 suppressed GLUD1 gene expression, decreased α-KG, increased ROS, and sensitized cells to anoikis.

• Item Type: Articles
• Status: Published
• Refereed: Yes
• Glasgow Author(s) Enlighten ID: Gottlieb, Professor Eyal and Zheng, Mr Liang
• Authors: Farris, J.C., Pifer, P. M., Zheng, L., Gottlieb, E., Denvir, J., and Frisch, S.M.
• College/School: College of Medical Veterinary and Life Sciences > School of Cancer Sciences
• Journal Name: Molecular Cancer Research
• Publisher: American Association for Cancer Research
• ISSN: 1541-7786
• ISSN (Online): 1557-3125
• Published Online: 01 June 2016