Protein arginine methyltransferase 5 confers the resistance of triple-negative breast cancer to nanoparticle albumin-bound paclitaxel by enhancing autophagy through the dimethylation of ULK1.

Abstract

Chemotherapy remains the major strategy for treating triple-negative breast cancer (TNBC); however, frequently acquired chemoresistance greatly limits the treatment outcomes. Protein arginine methyltransferase 5 (PRMT5), which modulates arginine methylation, is important in chemoresistance acquisition across various cancers. The function of PRMT5 in the development of chemoresistance in TNBC is still not well understood. This work focused on defining PRMT5's function in contributing to the chemoresistance in TNBC and demonstrating the possible mechanisms involved. Two TNBC cell lines resistant to nanoparticle albumin-bound paclitaxel (Nab-PTX), designated MDA-MB-231/R and MDA-MB-468/R, were developed. The expression of PRMT5 was markedly elevated in the cytoplasm of Nab-PTX-resistant cells accompanied with enhanced autophagy. The depletion of PRMT5 rendered these cells sensitive to Nab-PTX-evoked cytotoxicity. The autophagic flux was upregulated in Nab-PTX-resistant cells, which was markedly repressed by PRMT5 depletion. The dimethylation of ULK1 was markedly elevated in Nab-PTX-resistant cells, which was decreased by silencing PRMT5. Re-expression of PRMT5 in PRMT5-depleted cells restored the dimethylation and activation of ULK1 as well as the autophagic flux, while the catalytically-dead PRMT5 (R368A) mutant showed no significant effects. The depletion of PRMT5 rendered the subcutaneous tumors formed by Nab-PTX-resistant TNBC cells sensitive to Nab-PTX. The findings of this work illustrate that PRMT5 confers chemoresistance of TNBC by enhancing autophagy through dimethylation and the activation of ULK1, revealing a novel mechanism for understanding the acquisition of chemoresistance in TNBC. Targeting PRMT5 could be a viable approach for overcoming chemoresistance in the treatment of TNBC.