Targeting methyltransferase PRMT5 retards the carcinogenesis and metastasis of HNSCC via epigenetically inhibiting Twist1 transcription

Abstract

Protein arginine methyltransferase 5 (PRMT5) is an important type II arginine methyltransferase that can play roles in cancers in a highly tissue-specific manner, but its role in the carcinogenesis and metastasis of head and neck squamous cell carcinoma (HNSCC) remains unclear. Here, we detected PRMT5 expression in HNSCC tissues and performed series of in vivo and in vitro assays to investigate the function and mechanism of PRMT5 in HNSCC. We found that PRMT5 was overexpressed in dysplastic and cancer tissues, and associated with lymph node metastasis and worse patient survival. PRMT5 knockdown repressed the malignant phenotype of HNSCC cells in vitro and in vivo . PRMT5 specific inhibitor blocked the formation of precancerous lesion and HNSCC in 4NQO-induced tongue carcinogenesis model, prevented lymph node metastasis in tongue orthotopic xenograft model and inhibited cancer development in subcutaneous xenograft model and Patient-Derived tumor Xenograft (PDX) model. Mechanistically, PRMT5-catalyzed H3R2me2s promotes the enrichment of H3K4me3 in the Twist1 promoter region by recruiting WDR5, and subsequently activates the transcription of Twist1. The rescue experiments indicated that overexpressed Twist1 abrogated the inhibition of cell invasion induced by PRMT5 inhibitor. In summary, this study elucidates that PRMT5 inhibition could reduce H3K4me3-mediated Twist1 transcription and retard the carcinogenesis and metastasis of HNSCC.

Protein Arginine Methyltransferase 5 Functions via Interacting Proteins

“…PRMT5 promotes the metastasis of laryngeal carcinoma by activating Wnt4/β -catenin signaling pathway (Wang et al, 2020). Inhibition of PRMT5 reduces the transcription of Twist 1 mediated by H3K4me3 and delays the metastasis of squamous cell carcinoma of head and neck (Fan et al, 2020). Moreover, macrophage-capping protein (CAPG) has been shown to promote cancer metastasis, STC-1 enhances the invasion of cancer cells by activating PI3K pathway.…”

FOXD1 Regulates the Sensitivity of Cetuximab by Regulating the Expression of EGFR in Head and Neck Squamous Cell Cancer

“…The forkhead box (FOX) family, composed of proteins that share related winged helix-turn-helix DNA binding motifs, belongs to the “winged helix” superfamily [ 13 ]. FOX genes are widely present in the evolution of vertebrates and invertebrates, involved in many molecular cascades and regulation of biological functions, such as embryonic development, cell cycle regulation, early morning metabolism control, and signal pathway transduction [ 14 ]. FOXD1 dysfunction has been linked to different pathologies, which constitutes diagnostic biomarker and becomes a promising target for future treatment [ 14 ].…”

Ribavirin inhibits cell proliferation and metastasis and prolongs survival in soft tissue sarcomas by downregulating both protein arginine methyltransferases 1 and 5

“…1,49 Although PRMT5 is a major type II PRMTs that specifically deposits SDMA marks on histone H3 at arginine 8 (H3R8me2s) and histone H4 at arginine 3 (H4R3me2s), and these two marks are associated with transcriptional repression. [50][51][52] We demonstrated that inhibition of PRMT1 by ribavirin caused a significant decrease of PRMT1 enrichment, whereas inhibition of PRMT5 by ribavirin caused a significant increase of PRMT5 enrichment in VEGF gene. These findings suggested that ribavirin repressed transcription of VEGF through PRMT1 and PRMT5, and the VEGF gene regulated by PRMT1 and PRMT5 was further confirmed by measurement of its mRNA levels in ascites tumour treated with ribavirin.…”