Autophagy dictates sensitivity to PRMT5 inhibitor in breast cancer

Area of Science:

• Oncology
• Molecular Biology
• Cellular Biology

Background:

• Protein arginine methyltransferase 5 (PRMT5) is a potential cancer target with inhibitors in clinical trials.
• The regulation of PRMT5 inhibitor efficacy is not well understood.
• PRMT5 inhibition can trigger cytoprotective autophagy in cancer cells.

Purpose of the Study:

• To investigate how autophagy influences sensitivity to PRMT5 inhibitors.
• To elucidate the molecular mechanism of PRMT5-mediated autophagy regulation.
• To provide a rationale for combining PRMT5 and autophagy inhibitors in cancer treatment.

Main Methods:

• Genetic ablation and pharmacological inhibition of PRMT5.
• Assessment of autophagy induction and sensitivity to PRMT5 inhibitors.
• Analysis of ULK1 monomethylation at R532 by PRMT5.

Main Results:

• Autophagy blockage enhances cellular sensitivity to PRMT5 inhibitors in triple-negative breast cancer.
• PRMT5 inhibition induces cytoprotective autophagy.
• PRMT5 directly monomethylates ULK1 at R532, suppressing ULK1 activation and autophagy.
• ULK1 inhibition sensitizes cells to PRMT5 inhibition by blocking autophagy.

Conclusions:

• Autophagy is a key factor determining cellular response to PRMT5 inhibitors.
• PRMT5 regulates autophagy through ULK1 methylation, revealing a novel mechanism.
• Combining PRMT5 and autophagy inhibitors may be a promising therapeutic strategy for cancer.