TY - JOUR
T1 - Extracellular Acidic pH Activates the Sterol Regulatory Element-Binding Protein 2 to Promote Tumor Progression
AU - Kondo, Ayano
AU - Yamamoto, Shogo
AU - Nakaki, Ryo
AU - Shimamura, Teppei
AU - Hamakubo, Takao
AU - Sakai, Juro
AU - Kodama, Tatsuhiko
AU - Yoshida, Tetsuo
AU - Aburatani, Hiroyuki
AU - Osawa, Tsuyoshi
N1 - Funding Information:
We thank the members of the Division of Genome Science and Laboratory for Systems Biology and Medicine, RCAST, University of Tokyo. We especially thank Ms. Y. Hasegawa, Ms. A. Uchida, Ms. Y. Meguro, Ms. K. Shiina, Dr. H. Ueda, Dr. A. Okabe, Dr. M. Seki, Dr. A. Nonaka, Dr. S. Nomura, Mr. T. Fujita (LSBM, RCAST, The University of Tokyo), Dr. Y. Kanki (Radioisotope Center, The University of Tokyo), Dr. K. Tomizuka, and Dr. A. Kunisato (Innovative Technology Laboratories, Kyowa Hakko Kirin Co., Ltd.) for helpful discussions and support. This work was supported by Grant-in-Aid for Young Scientist (A) (26710005, T.O.), Grant-in-Aid for Scientific Research on Innovative Areas (26116711 and 16H01567, T.O.) and Grant-in-Aid for Challenging Exploratory Research (16K14605, T.O.) from the Ministry of Education, Culture, Sports, Science and Technology of Japan, the Takeda Science Foundation (T.O.), the Kowa Life Science Foundation (T.O.), and the Project for Cancer Research and Therapeutic Evolution (P-CREATE) from Japan Agency for Medical Research and Development, AMED (T.K., H.A., and T.O.).
Publisher Copyright:
© 2017 The Author(s)
PY - 2017/2/28
Y1 - 2017/2/28
N2 - 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.
AB - 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.
KW - acyl-CoA synthetase short-chain family member 2
KW - cancer metabolism
KW - epigenetics
KW - extracellular low pH
KW - hypoxia
KW - lacate
KW - nutrient starvation
KW - sterol regulatory element-binding protein 2
KW - tumor microenvironment
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U2 - 10.1016/j.celrep.2017.02.006
DO - 10.1016/j.celrep.2017.02.006
M3 - Article
C2 - 28249167
AN - SCOPUS:85014113083
SN - 2211-1247
VL - 18
SP - 2228
EP - 2242
JO - Cell Reports
JF - Cell Reports
IS - 9
ER -
