E2F1-driven CENPM expression promotes glycolytic reprogramming and tumorigenicity in glioblastoma.

Abstract

Centromere protein M (CENPM), traditionally associated with chromosome segregation, is now recognized for its significant role in cancer biology. Particularly in glioblastoma (GBM), where less is known about CENPM compared to other centromere proteins (CENPs), it appears crucially involved in regulating tumor cell proliferation, invasion, and metabolic reprogramming-key factors in GBM's aggressiveness. Initial analyses using the GEPIA database (TCGA/GTEx datasets) reveal distinct patterns of CENPM expression in GBM, suggesting its potential as a therapeutic target. Our study manipulated CENPM expression through shRNA-mediated knockdown and vector-based overexpression in GBM cell lines LN229 and U251. Knockdown resulted in a 50% reduction in cell proliferation and a 70% decrease in invasion, accompanied by diminished glycolytic markers such as glucose consumption, lactate production, and ATP levels. Conversely, overexpression of CENPM enhanced both metabolic activity and invasive capacities. The introduction of the glycolytic inhibitor 2-DG effectively reversed the effects of CENPM modulation, highlighting a dependency on glycolytic pathways. Moreover, we identified E2F1 as a key regulator of CENPM, linking it to GBM's metabolic alterations. In vivo studies using a BALB/c nude mouse xenograft model demonstrated that CENPM knockdown significantly inhibits tumor growth, with treated groups showing a 60% reduction in tumor volume over four weeks. These findings underscore the E2F1-CENPM axis as a promising target for therapeutic strategies, aiming to disrupt the metabolic and invasive pathways facilitated by CENPM in GBM. These insights establish a foundation for targeting the metabolic dependencies of tumor cells, potentially leading to innovative treatments for GBM.