<p>Centromere protein M (CENPM) promotes oncogenesis and serves as a prognostic biomarker in some cancers, but its implication in cutaneous melanoma is not clear. This study aimed to investigate the effect of targeting CENPM on cell proliferation, colony ability, apoptosis, invasion, migration, and BRAF inhibitor sensitivity, and its modification on Wnt/β-catenin, AKT, and P53 pathways in cutaneous melanoma. Cutaneous melanoma cell lines (A375 and SK-MEL-28) were transfected by CENPM siRNA (si-CENPM), followed by detections and treatment of various concentrations of dabrafenib and vemurafenib. Afterwards, 740Y-P (AKT activator) was added with or without si-CENPM transfection followed by detections. Gene Expression Profiling Interactive Analysis (GEPIA) public database was applied for clinical analysis. si-CENPM reduced cell proliferation, invasive cells and cell migration rate, but induced cell apoptosis rate in A375 and SK-MEL-28 cells. Meanwhile, si-CENPM decreased colony ability in A375 cells but didn’t change colony ability in SK-MEL-28 cells. However, si-CENPM did not change cell viability under each concentration or IC₅₀ value of BRAF inhibitors (dabrafenib and vemurafenib) in A375 and SK-MEL-28 cells. Interestingly, si-CENPM inactivated AKT pathway but less affected Wnt/β-catenin and P53 pathways in A375 and SK-MEL-28 cells. Afterwards, 740Y-P treatment attenuated the effect of si-CENPM on most of the above cellular functions in A375 and SK-MEL-28 cells. Clinically, GEPIA database revealed that CENPM was upregulated and correlated with worse overall survival in cutaneous melanoma patients. Targeting CENPM suppresses cutaneous melanoma growth and mobility by inactivating AKT pathway, indicating its potential as a treatment target.</p>