Journal
BIOCHIMICA ET BIOPHYSICA ACTA-MOLECULAR BASIS OF DISEASE
Volume 1866, Issue 1, Pages -Publisher
ELSEVIER
DOI: 10.1016/j.bbadis.2019.165576
Keywords
Lactate; GPR81; Snail; STAT3; Lung cancer
Funding
- National Natural Science Foundation of China [81872371]
- Anhui Provincial Natural Science Foundation [1708085MH203]
- Open Project Program of State Key Laboratory of Molecular Oncology [SKL-KF-2019-11]
- Natural Science Foundation of the Higher Education Institutions of Anhui Province [KJ2018A0248]
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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.
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