RBM14 drives prostate cancer metastasis via stabilizing HK2 mRNA to activate glycolysis and H3K18 lactylation

Metastasis is a leading cause of poor prognosis in prostate cancer (PCa), yet its underlying regulatory mechanisms remain incompletely understood. Following the establishment of highly invasive PC-3M cell lines, RBM14 expression was found to be significantly elevated in highly invasive cells. Furthermore, RBM14 was upregulated in PCa tissues and positively correlated with adverse clinicopathological features. Functional assays demonstrated that RBM14 significantly promoted PCa cell metastasis in vitro and in vivo. Mechanistically, RBM14 bound HK2 mRNA via its RRM1/2 domains to enhance HK2 stability, thereby upregulating HK2 expression. This increased HK2 level boosted PCa cells' glycolytic capacity, which in turn led to increased global lactylation, especially in histone H3 lysine 18 lactylation (H3K18la). The elevated H3K18la preferentially enriched at the promoters of metastasis-related genes, further upregulating their expression. Importantly, combining RBM14 knockdown with 2-DG exerted a synergistic inhibitory effect on PCa metastasis. Collectively, this study identifies RBM14 as a key regulator of PCa metastasis via the HK2-glycolysis-H3K18la axis, providing a potential therapeutic target for combating PCa metastasis.