Role of USP10/METTL3/CXCR4 Axis in Immunotherapy of Castration-Resistant Prostate Cancer

Wu  Chen; Lijun  Xu; Haibo  Deng; Zhenyan  Zhu; Dongrong  Yang

doi:10.18502/ijaai.v24i3.18683

Wu Chen Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China
Lijun Xu Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China
Haibo Deng Department of Urology, Suzhou Integrative Traditional Chinese and Western Medicine Hospital, Suzhou, China
Zhenyan Zhu Department of Urology, Suzhou Integrative Traditional Chinese and Western Medicine Hospital, Suzhou, China
Dongrong Yang Department of Urology, The Second Affiliated Hospital of Soochow University, Suzhou, China

DOI: https://doi.org/10.18502/ijaai.v24i3.18683

Keywords: Castration-resistant prostate neoplasms; CXCR4 receptor; METTL3 protein; USP10 protein

Abstract

The aim of this study was to investigate the role of the ubiquitin specific peptidase 10 (USP10/methyltransferase like 3 (METTL3)/C-X-C chemokine receptor type 4 (CXCR4) axis in immunotherapy of castration-resistant prostate cancer (CRPC).

Knockdown experiments were conducted in CRPC cell lines to assess the effect of targeting CXCR4 on cell proliferation invasion and migration. Coculture experiments of CXCR4 knockdown CRPC cells with THP1-M0 were performed to evaluate their impact on macrophage polarization and migration ability. With CD8⁺ T cells was conducted to assess their effects on CD8⁺T cell proliferation and apoptosis. CXCR4-overexpressing CRPC cells were treated with the JAK-2 specific inhibitor AG490 to assess the effect of CXCR4 through the JAK2/STAT3 pathway on CRPC. The mechanisms by which USP10 regulates CXCR4 expression through targeting METTL3 were explored through dataset analysis, bioinformatics prediction, and Western blot.

In CRPC tissues and cells, there was an observed increase in CXCR4 expression. Suppressing CXCR4 through knockdown methods resulted in the inhibition of CRPC cell growth, movement, and infiltration. Additionally, it led to a reduction in M2 polarization and the recruitment of Tohoku Hospital Pediatrics-1 (THP1) M0 macrophages, along with a mitigation of CD8⁺ T cell exhaustion. Dataset analysis, bioinformatics prediction, and Western blot validation indicated that CXCR4 activates the JAK2/STAT3 pathway to promote the expression of CCL2 and PD-L1, while USP10 promotes CXCR4 expression through METTL3.

Our study underscores the significance of the USP10/METTL3/CXCR4 axis in immunotherapy for CRPC and CXCR4 as a potential target for therapeutic intervention in CRPC treatment.