Targeting PRMT1-mediated SRSF1 methylation to suppress oncogenic exon inclusion events and breast tumorigenesis

Area of Science:

• Molecular Biology
• Cancer Research
• Epigenetics

Background:

• Protein arginine methyltransferase 1 (PRMT1) is implicated in breast tumorigenesis.
• The precise molecular mechanisms of PRMT1 in breast cancer are not fully elucidated.

Purpose of the Study:

• To investigate the role of PRMT1 in RNA alternative splicing in breast cancer.
• To identify PRMT1 targets and explore therapeutic strategies for breast cancer.

Main Methods:

• PRMT1 methylome profiling to identify methylation targets.
• Analysis of SRSF1 phosphorylation and RNA binding.
• Assessment of breast cancer cell growth inhibition by PRMT1 inhibitor (iPRMT1) alone and in combination therapy.

Main Results:

• PRMT1 critically regulates RNA alternative splicing, favoring exon inclusion.
• PRMT1 directly methylates SRSF1, impacting its phosphorylation, RNA binding, and promoting exon inclusion.
• PRMT1 overexpression correlates with increased SRSF1 methylation and aberrant splicing in breast tumors, supporting cancer cell growth.
• A selective PRMT1 inhibitor, iPRMT1, effectively inhibits PRMT1-mediated SRSF1 methylation, exon inclusion, and breast cancer cell proliferation.
• Combination therapy with iPRMT1 and SRSF1 phosphorylation inhibitors demonstrated an additive effect on suppressing cancer cell growth.

Conclusions:

• This study reveals a novel mechanism of PRMT1-driven RNA alternative splicing in breast cancer.
• PRMT1's role in regulating SRSF1 methylation and exon inclusion highlights its significance in breast cancer progression.
• PRMT1 represents a promising therapeutic target for breast cancer treatment.