MAT1A activation of glycolysis to promote NSCLC progression depends on stabilizing CCND1.

Abstract

Non-small cell lung cancer (NSCLC) remains a cause for concern as the leading cause of cancer-related death worldwide. Amidst ongoing debates on the role and mechanisms of methionine adenosyltransferase 1A (MAT1A) in cancer, our study sheds light on its significance in NSCLC. Leveraging TCGA database and immunohistochemical staining, we systematically analyzed MAT1A expression in NSCLC, uncovering its marked upregulation. To unravel the functional and mechanistic underpinnings, we implemented stable knockdown of MAT1A in NSCLC cell lines. Our findings converged to demonstrate that suppression of MAT1A expression effectively impeded the proliferation and migratory capabilities of NSCLC cells, while concurrently enhancing apoptosis. Mechanistically, we discovered that MAT1A depletion accelerated the degradation of CCND1, a key cell cycle regulator, through S-phase kinase-associated protein 2 (SKP2)-mediated ubiquitination. Notably, CCND1 emerged as a crucial MAT1A partner, jointly orchestrating glycolytic metabolism in NSCLC cells. This intricate interplay suggests that MAT1A promotes NSCLC progression by safeguarding CCND1 protein stability and activating glycolytic pathways, thereby sustaining tumorigenesis. In summary, our study not only identifies MAT1A as a prognostic marker for poor survival in NSCLC patients but also elucidates its mechanistic contributions to cancer progression. These findings pave the way for the development of targeted therapies aimed at disrupting the deleterious MAT1A-CCND1-glycolysis axis in NSCLC.