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

研究成果: Article査読

79 被引用数 (Scopus)

抄録

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.

本文言語English
ページ(範囲)2228-2242
ページ数15
ジャーナルCell Reports
18
9
DOI
出版ステータスPublished - 2017 2月 28
外部発表はい

ASJC Scopus subject areas

  • 生化学、遺伝学、分子生物学(全般)

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