Format

Send to

Choose Destination
Cell Rep. 2017 Feb 28;18(9):2228-2242. doi: 10.1016/j.celrep.2017.02.006.

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

Author information

1
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.
2
Division of Genome Science, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan.
3
Department of Systems Biology, Graduate School of Medicine, Nagoya University, 65 Tsurumai-cho, Showa-ku, Nagoya, 466-8550, Japan.
4
Department of Quantitative Biology and Medicine, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan.
5
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.
6
Laboratory for Systems Biology and Medicine, RCAST, The University of Tokyo, 4-6-1 Komaba, Meguro-ku, Tokyo, 153-8904, Japan.
7
Translational Research Unit, Kyowa Hakko Kirin Co., Ltd. 1188 Shimotogari, Nagaizumi-cho, Sunto-gun, Shizuoka 441-8731, Japan.
8
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.
9
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.

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.

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

PMID:
28249167
DOI:
10.1016/j.celrep.2017.02.006
[Indexed for MEDLINE]
Free full text

Supplemental Content

Full text links

Icon for Elsevier Science
Loading ...
Support Center