Role of Protein Arginine Methyltransferase 5 (PRMT5) in WNT/β--CATENIN proliferative signaling in breast cancer

Abstract

Protein arginine methyltransferase 5 (PRMT5) activity is dysregulated in many aggressive cancers and its enhanced levels are associated with increased tumor growth and survival. In this study, we show that PRMT5 is overexpressed in breast cancer cell lines, and that it promotes WNT/B-CATENIN proliferative signaling through epigenetic silencing of pathway antagonists, DKK1 and DKK3, by binding to their promoter and inducing symmetric dimethylation of H3R8 and H4R3, leading to enhanced expression of c-MYC, CYCLIN D1 and SURVIVIN. Our findings also show that PRMT5 inhibition using compound 5 (CMP5), reduces PRMT5 recruitment and PRMT5-induced epigenetic marks in the promoter regions of DKK1 and DKK3, which consequently results in reduced expression of CYCLIN D1 and SURVIVIN. Furthermore, CMP5 treatment either alone or in combination with 5-Azacytidine and Trichostatin A restored expression of DKK1 and DKK3 in TNBCs. In addition, PRMT5 inhibition in TNBCs inhibited AKT/mTOR signaling by reducing phosphorylation of AKT and mTOR at Ser473 and Ser2448, respectively. These molecular changes were associated with reduced proliferation, migration and invasion of breast cancer cells, and induced their death.