PRMT5-Mediated ALKBH5 Methylation Promotes Colorectal Cancer Immune Evasion via Increasing CD276 Expression.

Area of Science:

• Oncology
• Molecular Biology
• Immunology

Background:

• Protein arginine methyltransferase 5 (PRMT5) is implicated in numerous diseases, including cancer.
• PRMT5-specific inhibitors like GSK3326595 are under clinical investigation for cancer therapy.
• The precise role of PRMT5 in colorectal cancer (CRC) progression is not fully understood.

Purpose of the Study:

• To elucidate the mechanism by which PRMT5 promotes malignant progression in colorectal cancer.
• To investigate the interplay between PRMT5, ALKBH5, and CD276 in CRC.
• To evaluate the therapeutic potential of targeting the PRMT5-ALKBH5-CD276 axis in CRC.

Main Methods:

• Investigated PRMT5-mediated modification of ALKBH5 using biochemical assays.
• Assessed the impact of ALKBH5 on CD276 expression and stability via RNA analysis.
• Evaluated the effect of CD276 upregulation on cytotoxic T-cell function and CRC immune evasion.
• Utilized in vitro and in vivo models to study the PRMT5-ALKBH5-CD276 axis in CRC.
• Examined the efficacy of combining a PRMT5 inhibitor with an anti-PD1 antibody in CRC models.

Main Results:

• PRMT5 directly catalyzes symmetric dimethylation of ALKBH5 at R316 (meR316-ALKBH5), promoting its degradation.
• Reduced ALKBH5 levels lead to increased CD276 mRNA stability and expression in CRC cells.
• Upregulated CD276 inhibits cytotoxic T-cell function, contributing to CRC immune evasion.
• PRMT5-mediated meR316-ALKBH5 enhances CD276 expression and CRC immune evasion both in vitro and in vivo.
• A strong correlation exists between meR316-ALKBH5 levels and poor outcomes in CRC patients.
• Combination therapy with GSK3326595 (PRMT5 inhibitor) and an anti-PD1 antibody significantly halted CRC progression.

Conclusions:

• PRMT5 promotes CRC progression and immune evasion through the meR316-ALKBH5-CD276 axis.
• Targeting the PRMT5-meR316-ALKBH5-CD276 pathway represents a potential therapeutic strategy for CRC.
• Combined inhibition of PRMT5 and PD-1 offers a promising approach for treating colorectal cancer.