CMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

Linchong Sun, Libing Song, Qianfen Wan, Gongwei Wu, Xinghua Li, Yinghui Wang, Jin Wang, Zhaoji Liu, Xiuying Zhong, Xiaoping He, Shengqi Shen, Xin Pan, Ailing Li, Yulan Wang, Ping Gao, Huiru Tang, Huafeng Zhang

Research output: Contribution to journalArticlepeer-review

Abstract

Cancer cells are known to undergo metabolic reprogramming to sustain survival and rapid proliferation, however, it remains to be fully elucidated how oncogenic lesions coordinate the metabolic switch under various stressed conditions. Here we show that deprivation of glucose or glutamine, two major nutrition sources for cancer cells, dramatically activated serine biosynthesis pathway (SSP) that was accompanied by elevated cMyc expression. We further identified that cMyc stimulated SSP activation by transcriptionally upregulating expression of multiple SSP enzymes. Moreover, we demonstrated that SSP activation facilitated by cMyc led to elevated glutathione (GSH) production, cell cycle progression and nucleic acid synthesis, which are essential for cell survival and proliferation especially under nutrient-deprived conditions. We further uncovered that phosphoserine phosphatase (PSPH), the final rate-limiting enzyme of the SSP pathway, is critical for cMyc-driven cancer progression both in vitro and in vivo, and importantly, aberrant expression of PSPH is highly correlated with mortality in hepatocellular carcinoma (HCC) patients, suggesting a potential causal relation between this cMyc-regulated enzyme, or SSP activation in general, and cancer development. Taken together, our results reveal that aberrant expression of cMyc leads to the enhanced SSP activation, an essential part of metabolic switch, to facilitate cancer progression under nutrient-deprived conditions.

Original languageEnglish (US)
Pages (from-to)429-444
Number of pages16
JournalCell Research
Volume25
Issue number4
DOIs
StatePublished - Apr 8 2015

Keywords

  • CMyc
  • Cancer
  • Metabolism
  • PSPH
  • SSP

ASJC Scopus subject areas

  • Molecular Biology
  • Cell Biology

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