Targeting PRMT5- FOXM1 axis inhibits pyrimidine metabolism to impede the progression of oral leukoplakia and squamous cell carcinoma

Oral leukoplakia (OLK), as one of oral latent malignant diseases (OPMDs), is easily transformed into oral squamous cell carcinoma (OSCC). A critical hallmark of cancer development is the up-regulation of nucleotide metabolism, which fulfills the demands of unchecked cellular proliferation. Protein arginine methyltransferase 5 (PRMT5) has been implicated in the pathogenesis of various diseases, including OSCC. However, the specific regulatory role of PRMT5 in nucleotide metabolism, particularly pyrimidine metabolism, remains inadequately understood. Here, we observed that the targeted inhibition of PRMT5 markedly reduced the proliferation, migration, and invasion of dysplastic oral keratinocyte (DOK) cells. RNA-seq and metabolomics results showed that targeting PRMT5 significantly inhibited pyrimidine metabolism. The mechanism observed in both DOK and OSCC cell lines is that PRMT5 promotes the activation of the transcription factor FOXM1 through H3R2me2s-K4me3, and collaborates with FOXM1 to enhance the expression of TK1, RRM2, TYMS, and CAD, thereby activating the pyrimidine metabolic pathway. Animal experiments corroborate that the inhibition of PRMT5 and FOXM1 suppresses the proliferation of OSCC tumors. Furthermore, supplementing exogenous dNTPs can partially mitigate the suppression of proliferation, invasion, and migration caused by targeting PRMT5. Consequently, our study suggests that PRMT5 augments pyrimidine metabolism through the epigenetic activation of FOXM1, thereby promoting the progression of OLK and OSCC. Targeted interventions against PRMT5 or FOXM1 are considered promising therapeutic strategies for the treatment of OLK and OSCC.