MPC1 deficiency promotes melanoma progression via Wnt/β-catenin signaling

Melanoma represents the most aggressive and lethal form of skin cancer with high metastatic potential and elucidating the mechanisms underlying its progression is essential for developing effective therapies. The mitochondrial pyruvate carrier 1 (MPC1) is critical in linking glycolysis and oxidative phosphorylation, which has also been implicated in the pathogenesis of various cancers, yet its role in melanoma progression remains poorly understood. In this study, we found that MPC1 was markedly downregulated in both melanoma cell lines and tissues compared to control, and the alteration was more prominent in metastatic stage. Functional studies revealed that MPC1 deficiency enhanced melanoma cell proliferation, migration, and invasion in vitro and augmented melanoma metastasis in vivo. Mechanistically, RNA sequencing and subsequent functional study have demonstrated that MPC1 suppressed the activation of Wnt/β-catenin pathway by regulating DKK3, a key Wnt antagonist. Furthermore, pharmacologic inhibition of Wnt/β-catenin abrogated the pro-tumorigenic effects of MPC1 knockdown both in vitro and in vivo. Collectively, these data demonstrated that MPC1 deficiency promotes melanoma progression via Wnt/β-catenin signaling that is associated with DKK3 regulation. Targeting MPC1-Wnt/β-catenin axis may represent a novel therapeutic strategy for advanced melanoma treatment.