A lactate-induced Snail/STAT3 pathway drives GPR81 expression in lung cancer cells

BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE

卷:1866

Article

Xie, Qiang^1,2,3  Zhu, Zhanzhan^1,2,3  He, Yuanpeng^1,4  Zhang, Zhijian^1,5  Zhang, Yao⁶  Wang, Yixuan⁴  Luo, Jincheng^1,4  Peng, Tianchou^1,4  Cheng, Feng^1,6  Gao, Jiguang^1,2,5  Cao, Yuxiang^1,6  Wei, Huijun^1,6  Wu, Zhihao^1,5,6 

[1] Wannan Med Coll, Res Lab Tumor Microenvironm, Wuhu 241001, Peoples R China

[2] Wannan Med Coll, Sch Pharm, Wuhu 241001, Peoples R China

[3] Wannan Med Coll, Anhui Higher Educ Inst, Key Lab Noncoding RNA Transformat Res, Wuhu 241001, Peoples R China

[4] Wannan Med Coll, Sch Clin Med, Wuhu 241001, Peoples R China

[5] Wannan Med Coll, Sch Preclin Med, Wuhu 241001, Peoples R China

[6] Wannan Med Coll, Anhui Prov Key Lab Act Biol Macromol Res, Wuhu 241001, Peoples R China

关键词: Lactate;    GPR81;    Snail;    STAT3;    Lung cancer;   

DOI  :  10.1016/j.bbadis.2019.165576

来源: Elsevier

【 摘 要 】

Highly expressed G protein-coupled receptor 81 (GPR81), a receptor for lactate, is emerging as a critical regulator of tumor growth and metastasis. However, the mechanistic basis for its highly expression in cancer cells remains elusive. Here we report that tumor-derived lactate transcriptionally regulates GPR81 expression. We demonstrated that the transcriptional response of GPR81 to lactate is mediated by Signal transducer and activator of transcription 3 (STAT3). Mechanistically, lactate upregulates transcriptional factor Snail and induces the assembly of Snail/EZH2/STAT3 complex. Within this ternary complex, STAT3 activity is strongly enhanced. Consequently, the activated STAT3 by lactate directly binds GPR81 promoter and activates its expression. These findings shed light on the transcriptional mechanism by which GPR81 expression is regulated in cancer cells, and provides mechanistic insight into how aberrant signaling and continually high lactate levels due to metabolic switch may yield a feed-forward/self-enabling loop to promote tumor progression.

【 授权许可】

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