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

• Published in: Cell reports (Cambridge) Vol. 18; no. 9; pp. 2228 - 2242
• Main Authors: Kondo, Ayano, Yamamoto, Shogo, Nakaki, Ryo, Shimamura, Teppei, Hamakubo, Takao, Sakai, Juro, Kodama, Tatsuhiko, Yoshida, Tetsuo, Aburatani, Hiroyuki, Osawa, Tsuyoshi
• Format: Journal Article
• Language: English
• Published: United States Elsevier Inc 28.02.2017; Elsevier
• Subjects: Acetate-CoA Ligase - metabolism; acyl-CoA synthetase short-chain family member 2; Animals; cancer metabolism; Cell Line, Tumor; Cell Nucleus - metabolism; Cell Proliferation - physiology; Cholesterol - metabolism; Disease Progression; epigenetics; extracellular low pH; HeLa Cells; Humans; Hydrogen-Ion Concentration; hypoxia; lacate; Mice; Mice, SCID; Neoplasms - metabolism; Neoplasms - pathology; nutrient starvation; Promoter Regions, Genetic - physiology; Protein Transport - physiology; Sterol Regulatory Element Binding Protein 2 - metabolism; sterol regulatory element-binding protein 2; tumor microenvironment; Up-Regulation - physiology; cancer metabolism; hypoxia; extracellular low pH; lacate; nutrient starvation; sterol regulatory element-binding protein 2; tumor microenvironment; acyl-CoA synthetase short-chain family member 2; epigenetics
• ISSN: 2211-1247; 2211-1247
• DOI: 10.1016/j.celrep.2017.02.006

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. [Display omitted] •Cellular responses to low pH were different from hypoxia and nutrient starvation•Extracellular acidic pH activates SREBP2 as a transcriptional regulator•SREBP2 increases cholesterol biosynthetic genes under low pH•pH-regulated SREBP2 target genes (e.g., ACSS2) affect tumor growth and malignancy Kondo et al. find that extracellular acidic pH induces different cellular responses than hypoxia and nutrient starvation. SREBP2 is a key transcriptional regulator of cholesterol biosynthetic genes and ACSS2 in response to extracellular acidification. SREBP2 target genes increase tumor growth in low pH and correlate with decreased survival in patients.