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

被引：151

作者：

Kondo, Ayano ^{[1
,2
]}

Yamamoto, Shogo ^{[1
]}

Nakaki, Ryo ^{[1
]}

Shimamura, Teppei ^{[3
]}

Hamakubo, Takao ^{[4
]}

Sakai, Juro ^{[5
,6
]}

Kodama, Tatsuhiko ^{[7
]}

Yoshida, Tetsuo ^{[8
]}

Aburatani, Hiroyuki ^{[1
,6
]}

Osawa, Tsuyoshi ^{[6
,7
]}

机构：

[1] Univ Tokyo, Div Genome Sci, RCAST, Meguro Ku, 4-6-1 Komaba, Tokyo 1538904, Japan

[2] Kyowa Hakko Kirin Co Ltd, Innovat Technol Labs, 3-6-6 Asahimachi, Machida, Tokyo 1948533, Japan

[3] Nagoya Univ, Grad Sch Med, Dept Syst Biol, Showa Ku, 65 Tsurumai Cho, Nagoya, Aichi 4668550, Japan

[4] Univ Tokyo, RCAST, Dept Quantitat Biol & Med, Meguro Ku, 4-6-1 Komaba, Tokyo 1538904, Japan

[5] Univ Tokyo, RCAST, Div Metab Med, Meguro Ku, 4-6-1 Komaba, Tokyo 1538904, Japan

[6] Univ Tokyo, Fac Med, Ctr Dis Biol & Integrat Med, TSBMI, Tokyo 1138655, Japan

[7] Univ Tokyo, RCAST, Lab Syst Biol & Med, Meguro Ku, 4-6-1 Komaba, Tokyo 1538904, Japan

[8] Kyowa Hakko Kirin Co Ltd, Translat Res Unit, 1188 Shimotogari, Nagaizumi, Shizuoka 4418731, Japan

来源：

CELL REPORTS | 2017年 / 18卷 / 09期

关键词：

INTRACELLULAR PH; HUMAN GLIOBLASTOMA; CANCER; CHOLESTEROL; ACETATE; GROWTH; CELLS; METABOLISM; EXPRESSION; SREBPS;

D O I：

10.1016/j.celrep.2017.02.006

中图分类号：

Q2 [细胞生物学];

学科分类号：

071009 ; 090102 ;

摘要：

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.

引用

页码：2228 / 2242

页数：15

共 43 条

[1] The SREBP pathway: Regulation of cholesterol metabolism by proteolysis of a membrane-bound transcription factor [J].