Extracellular Acidic pH Activates the Sterol Regulatory Element-Binding Protein 2 to Promote Tumor Progression

Ayano Kondo, Shogo Yamamoto, Ryo Nakaki, Teppei Shimamura, Takao Hamakubo, Juro Sakai, Tatsuhiko Kodama, Tetsuo Yoshida, Hiroyuki Aburatani, Tsuyoshi Osawa

Research output: Contribution to journalArticlepeer-review

52 Citations (Scopus)

Abstract

Conditions of the tumor microenvironment, such as hypoxia and nutrient starvation, play critical roles in cancer progression. However, the role of acidic extracellular pH in cancer progression is not studied as extensively as that of hypoxia. Here, we show that extracellular acidic pH (pH 6.8) triggered activation of sterol regulatory element-binding protein 2 (SREBP2) by stimulating nuclear translocation and promoter binding to its targets, along with intracellular acidification. Interestingly, inhibition of SREBP2, but not SREBP1, suppressed the upregulation of low pH-induced cholesterol biosynthesis-related genes. Moreover, acyl-CoA synthetase short-chain family member 2 (ACSS2), a direct SREBP2 target, provided a growth advantage to cancer cells under acidic pH. Furthermore, acidic pH-responsive SREBP2 target genes were associated with reduced overall survival of cancer patients. Thus, our findings show that SREBP2 is a key transcriptional regulator of metabolic genes and progression of cancer cells, partly in response to extracellular acidification.

Original languageEnglish
Pages (from-to)2228-2242
Number of pages15
JournalCell Reports
Volume18
Issue number9
DOIs
Publication statusPublished - 2017 Feb 28

Keywords

  • acyl-CoA synthetase short-chain family member 2
  • cancer metabolism
  • epigenetics
  • extracellular low pH
  • hypoxia
  • lacate
  • nutrient starvation
  • sterol regulatory element-binding protein 2
  • tumor microenvironment

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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