GPR176 Promotes Cancer Progression by Interacting with G Protein GNAS to Restrain Cell Mitophagy in Colorectal Cancer

Abstract GPR176 belongs to the G protein‐coupled receptor superfamily, which responds to external stimuli and regulates cancer progression, but its role in colorectal cancer (CRC) remains unclear. In the present study, expression analyses of GPR176 are performed in patients with colorectal cancer. Genetic mouse models of CRC coupled with Gpr176‐deficiency are investigated, and in vivo and in vitro treatments are conducted. A positive correlation between GPR176 upregulation and the proliferation and poor overall survival of CRC is demonstrated. GPR176 is confirmed to activate the cAMP/PKA signaling pathway and modulate mitophagy, promoting CRC oncogenesis and development. Mechanistically, the G protein GNAS is recruited intracellularly to transduce and amplify extracellular signals from GPR176. A homolog model tool confirmed that GPR176 recruits GNAS intracellularly via its transmembrane helix 3‐intracellular loop 2 domain. The GPR176/GNAS complex inhibits mitophagy via the cAMP/PKA/BNIP3L axis, thereby promoting the tumorigenesis and progression of CRC.