Loss of SETD2 Induces a Metabolic Switch in Renal Cell Carcinoma Cell Lines toward Enhanced Oxidative Phosphorylation

Jingping Liu, Paul D. Hanavan, Katon Kras, Yvette W. Ruiz, Erik P Castle, Douglas F. Lake, Xianfeng Chen, Daniel O'Brien, Huijun Luo, Keith D Robertson, Haiwei Gu, Thai H Ho

Research output: Contribution to journalArticle

5 Scopus citations

Abstract

SETD2, a histone H3 lysine trimethyltransferase, is frequently inactivated and associated with recurrence of clear cell renal cell carcinoma (ccRCC). However, the impact of SETD2 loss on metabolic alterations in ccRCC is still unclear. In this study, SETD2 null isogenic 38E/38F clones derived from 786-O cells were generated by zinc finger nucleases, and subsequent metabolic, genomic, and cellular phenotypic changes were analyzed by targeted metabolomics, RNA sequencing, and biological methods, respectively. Our results showed that compared with parental 786-O cells, 38E/38F cells had elevated levels of MTT/Alamar blue levels, ATP, glycolytic/mitochondrial respiratory capacity, citrate synthase (CS) activity, and TCA metabolites such as aspartate, malate, succinate, fumarate, and α-ketoglutarate. The 38E/38F cells also utilized alternative sources beyond pyruvate to generate acetyl-CoA for the TCA cycle. Moreover, 38E/38F cells showed disturbed gene networks mainly related to mitochondrial metabolism and the oxidation of fatty acids and glucose, which was associated with increased PGC1α, mitochondrial mass, and cellular size/complexity. Our results indicate that SETD2 deficiency induces a metabolic switch toward enhanced oxidative phosphorylation in ccRCC, which can be related to PGC1α-mediated metabolic networks. Therefore, this current study lays the foundation for the further development of a global metabolic analysis of cancer cells in individual patients, which ultimately will have significant potential for the discovery of novel therapeutics and precision medicine in SETD2-inactivated ccRCC.

Original languageEnglish (US)
Pages (from-to)331-340
Number of pages10
JournalJournal of Proteome Research
Volume18
Issue number1
DOIs
StatePublished - Jan 4 2019

Keywords

  • clear cell renal cell carcinoma (ccRCC)
  • mitochondria
  • oxidative phosphorylation
  • PGC1α
  • SETD2

ASJC Scopus subject areas

  • Biochemistry
  • Chemistry(all)

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