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

Sen Meng1,2, Hao Liu2, Jiayu Xu3

  • 1Cancer Institute, Xuzhou Medical University, Xuzhou, Jiangsu, China.

Research (Washington, D.C.)
|January 9, 2025
PubMed

Insights

Protein arginine methyltransferase 5 (PRMT5) promotes colorectal cancer (CRC) by enhancing CD276 expression via ALKBH5 modification. Targeting this axis, combined with anti-PD1 therapy, shows promise for CRC treatment.

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.

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