title: Extracellular Acidic pH Activates the Sterol Regulatory Element-Binding Protein 2 to Promote Tumor Progression.
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.
authors.affiliation: Division of Genome Science, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan; Innovative Technology Laboratories, Kyowa Hakko Kirin Co., Ltd. 3-6-6 Asahimachi, Machida, Tokyo, 194-8533, Japan.
authors.forename: Ayano
authors.initials: A
authors.lastname: Kondo
authors.affiliation: Division of Genome Science, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan.
authors.forename: Shogo
authors.initials: S
authors.lastname: Yamamoto
authors.affiliation: Division of Genome Science, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan.
authors.forename: Ryo
authors.initials: R
authors.lastname: Nakaki
authors.affiliation: Department of Systems Biology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
authors.forename: Teppei
authors.initials: T
authors.lastname: Shimamura
authors.affiliation: Department of Quantitative Biology and Medicine, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan.
authors.forename: Takao
authors.initials: T
authors.lastname: Hamakubo
authors.affiliation: Division of Metabolic Medicine, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan; The Translational Systems Biology and Medicine Initiative (TSBMI), Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan.
authors.forename: Juro
authors.initials: J
authors.lastname: Sakai
authors.affiliation: Laboratory for Systems Biology and Medicine, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan.
authors.forename: Tatsuhiko
authors.initials: T
authors.lastname: Kodama
authors.affiliation: Translational Research Unit, Kyowa Hakko Kirin Co., Ltd. 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 441-8731, Japan.
authors.forename: Tetsuo
authors.initials: T
authors.lastname: Yoshida
authors.affiliation: Division of Genome Science, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan; The Translational Systems Biology and Medicine Initiative (TSBMI), Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan. Electronic address: haburata-tky@umin.ac.jp.
authors.forename: Hiroyuki
authors.initials: H
authors.lastname: Aburatani
authors.affiliation: The Translational Systems Biology and Medicine Initiative (TSBMI), Center for Disease Biology and Integrative Medicine, Faculty of Medicine, The University of Tokyo, Tokyo 113-8655, Japan; Laboratory for Systems Biology and Medicine, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan. Electronic address: osawa@lsbm.org.
authors.forename: Tsuyoshi
authors.initials: T
authors.lastname: Osawa
mesh_terms: D000106:Acetate-CoA Ligase / Q000378:metabolism; D000818:Animals; D045744:Cell Line, Tumor; D002467:Cell Nucleus / Q000378:metabolism; D049109:Cell Proliferation / Q000502:physiology; D002784:Cholesterol / Q000378:metabolism; D018450:Disease Progression; D006367:HeLa Cells; D006801:Humans; D006863:Hydrogen-Ion Concentration; D051379:Mice; D016513:Mice, SCID; D009369:Neoplasms / Q000378:metabolism* / Q000473:pathology*; D011401:Promoter Regions, Genetic / Q000502:physiology; D021381:Protein Transport / Q000502:physiology; D051782:Sterol Regulatory Element Binding Protein 2 / Q000378:metabolism*; D015854:Up-Regulation / Q000502:physiology
chemical_list: C497390:SREBF2 protein, human; D051782:Sterol Regulatory Element Binding Protein 2; D002784:Cholesterol; C000595379:ACSS2 protein, human; D000106:Acetate-CoA Ligase
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