TY - JOUR AU - Mohapatra, Pallavi AU - Shriwas, Omprakash AU - Mohanty, Sibasish AU - Ghosh, Arup AU - Smita, Shuchi AU - Kaushik, Sandeep Rai AU - Arya, Rakesh AU - Rath, Rachna AU - Das Majumdar, Saroj Kumar AU - Muduly, Dillip Kumar AU - Raghav, Sunil K. AU - Nanda, Ranjan K. AU - Dash, Rupesh T1 - CMTM6 drives cisplatin resistance by regulating Wnt signaling through the ENO-1/AKT/GSK3β axis PY - 2021/02/22/ AB - Rewiring tumor cells to undergo drug-induced apoptosis is a promising way to overcome chemoresistance. Therefore, identifying causative factors for chemoresistance is of high importance. Unbiased global proteome profiling of sensitive, early, and late cisplatin-resistant oral squamous cell carcinoma (OSCC) lines identified CMTM6 as a top-ranked upregulated protein. Analyses of OSCC patient tumor samples demonstrated significantly higher CMTM6 expression in chemotherapy (CT) nonresponders as compared with CT responders. In addition, a significant association between higher CMTM6 expression and poorer relapse-free survival in esophageal squamous cell carcinoma, head and neck squamous cell carcinoma, and lung squamous cell carcinoma was observed from Kaplan-Meier plot analysis. Stable knockdown (KD) of CMTM6 restored cisplatin-mediated cell death in chemoresistant OSCC lines. Upon CMTM6 overexpression in CMTM6-KD lines, the cisplatin-resistant phenotype was rescued. The patient-derived cell xenograft model of chemoresistant OSCC displaying CMTM6 depletion restored the cisplatin-induced cell death and tumor burden substantially. The transcriptome analysis of CMTM6-KD and control chemoresistant cells depicted enrichment of the Wnt signaling pathway. We demonstrated that CMTM6 interaction with membrane-bound Enolase-1 stabilized its expression, leading to activation of Wnt signaling mediated by AKT–glycogen synthase kinase-3β. CMTM6 has been identified as a stabilizer of programmed cell death ligand 1. Therefore, as CMTM6 facilitates tumor cells for immune evasion and mediates cisplatin resistance, it could be a promising therapeutic target for treating therapy-resistant OSCC. JF - JCI Insight JA - JCI Insight SN - 2379-3708 DO - 10.1172/jci.insight.143643 VL - 6 IS - 4 UR - https://doi.org/10.1172/jci.insight.143643 PB - The American Society for Clinical Investigation ER -