Dataset Information

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

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE299188 | GEO | 2026/06/01

REPOSITORIES: GEO

ACCESS DATA

Similar Datasets

Project description:Radioresistance is a major obstacle to the successful treatment of oral squamous cell carcinoma (OSCC). To help overcome this issue, we have developed clinically relevant radioresistant (CRR) cell lines, generated by irradiating parental cells over time, which are useful for OSCC research. In the present study, we conducted gene expression analysis using CRR cells and their parental lines to investigate the regulation of radioresistance in OSCC cells. Based on gene expression changes over time in CRR cells and parental lines subjected to irradiation, forkhead box M1 (FOXM1) was selected for further analysis in terms of its expression OSCC cell lines, including CRR cell lines, and clinical specimens. We suppressed or upregulated the expression of FOXM1 in OSCC cell lines, including CRR cell lines, and examined radiosensitivity, DNA damage, and cell viability under various conditions. The molecular network regulating radiotolerance was also investigated, especially the redox pathway, and the radiosensitizing effect of FOXM1 inhibitors was examined as a potential therapeutic application. We found that FOXM1 was not expressed in normal human keratinocytes but was expressed in several OSCC cell types. The expression of FOXM1 was upregulated in CRR cells compared with that detected in the parental cell lines. In clinical specimens, FOXM1 expression was upregulated in cells that survived irradiation. FOXM1-specific siRNA treatment increased radiosensitivity, whereas FOXM1 overexpression decreased radiosensitivity, and DNA damage was altered significantly under both conditions as well as the levels of redox-related molecules and reactive oxygen species production. Treatment with the FOXM1 inhibitor thiostrepton had a radiosensitizing effect and overcame radiotolerance in CRR cells. According to these results, the FOXM1-mediated regulation of reactive oxygen species could be a novel therapeutic target for the treatment of radioresistant OSCC; thus, treatment strategies targeting this axis might overcome radioresistance in this disease.

Dataset Information

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

Similar Datasets

OmicsDI is part of the ELIXIR infrastructure

Tweets