PRRC2A-mediated m6A modification on NCOA4 promotes thymic epithelial tumor progression through PKM2-induced glycolysis
TL;DR
In vivo experiments showed that inhibition of PRRC2A suppressed tumor growth and metastasis in TETs, while combined treatment with the PKM2 inhibitor C599 and PRRC2A knockdown produced enhanced antitumor effects, suggesting that the PRRC2A-NCOA4-PKM2 axis represents a promising therapeutic target.
Abstract
Thymic epithelial tumors (TETs) are heterogeneous neoplasms. While most early-stage cases are curable after resection, advanced or aggressive subtypes have limited treatment options and poor outcomes. The molecular mechanisms underlying their metabolic reprogramming remain poorly understood. Proline-rich Coiled-coil 2a (PRRC2A), a N6-methyladenosine (m6A) reader protein, is significantly upregulated in TET tissues and is associated with poor clinical outcomes. Multi-omics analyses and molecular experiments revealed that PRRC2A binds to m6A-modified sites within the NCOA4 mRNA, thereby stabilizing NCOA4 transcripts and enhancing its protein expression. Elevated NCOA4 interacts with PKM2, a rate-limiting glycolytic enzyme, resulting in increased glycolysis and promoting TETs progression. In vivo experiments showed that inhibition of PRRC2A suppressed tumor growth and metastasis in TETs, while combined treatment with the PKM2 inhibitor C599 and PRRC2A knockdown produced enhanced antitumor effects. These findings provide novel insights into the glycolytic metabolic regulation of TETs and suggest that the PRRC2A-NCOA4-PKM2 axis represents a promising therapeutic target.