2. Academic Validation
  3. Inhibition of PRMT5 moderately suppresses prostate cancer growth in vivo but enhances its response to immunotherapy

Inhibition of PRMT5 moderately suppresses prostate cancer growth in vivo but enhances its response to immunotherapy

  • Cancer Lett. 2024 Oct 10:602:217214. doi: 10.1016/j.canlet.2024.217214.
Qinju He 1,  Yuanzhen Zhang 1,  Wenchao Li 2,  Saisai Chen 2,  Jiangling Xiong 3,  Ruizhe Zhao 4,  Kai Yuan 5,  Qiang Hu 6,  Song Liu 6,  Guozhen Gao 7,  Mark T Bedford 7,  Dean G Tang 8,  Bin Xu 9,  Cheng Zou 10,  Dingxiao Zhang 11
Affiliations

Affiliations

  • 1 Affiliated Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China; Hunan Key Laboratory of Animal Models and Molecular Medicine, Hunan University, Changsha, 410082, China.
  • 2 Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, China.
  • 3 Hunan Key Laboratory of Animal Models and Molecular Medicine, Hunan University, Changsha, 410082, China.
  • 4 Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA; Current Address: Department of Urology, First Affiliated Hospital of Nanjing Medical University, Nanjing, 210029, China.
  • 5 Hunan Key Laboratory of Molecular Precision Medicine, Department of Oncology, Xiangya Hospital, Central South University, Changsha, Hunan, 410000, China.
  • 6 Department of Biostatistics and Bioinformatics, Roswell Park Comprehensive Cancer Center, Buffalo, 14263, New York, USA.
  • 7 Department of Epigenetics and Molecular Carcinogenesis, The University of Texas MD Anderson Cancer Center, Houston, TX, 77030, USA.
  • 8 Department of Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, 14263, USA.
  • 9 Department of Urology, Affiliated Zhongda Hospital of Southeast University, Nanjing, 210009, China. Electronic address: njxbseu@seu.edu.cn.
  • 10 Affiliated Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China; Hunan Key Laboratory of Animal Models and Molecular Medicine, Hunan University, Changsha, 410082, China; Shenzhen Research Institute, Hunan University, Shenzhen, 518000, China. Electronic address: zoucheng@hnu.edu.cn.
  • 11 Affiliated Hospital of Hunan University, School of Biomedical Sciences, Hunan University, Changsha, China; Hunan Key Laboratory of Animal Models and Molecular Medicine, Hunan University, Changsha, 410082, China; Shenzhen Research Institute, Hunan University, Shenzhen, 518000, China. Electronic address: zdx1980@hnu.edu.cn.
PMID: 39218291 DOI: 10.1016/j.canlet.2024.217214
Abstract

Protein arginine methylation is a common post-translational modification (PTM) catalyzed by nine protein arginine methyltransferases (PRMTs). As the major symmetric arginine methyltransferase that methylates both histone and non-histone substrates, PRMT5 plays key roles in a number of biological processes critical for development and tumorigenesis. PRMT5 overexpression has been reported in multiple Cancer types including prostate Cancer (PCa), but the exact biological and mechanistic understanding of PRMT5 in aggressive PCa remains ill-defined. Here, we show that PRMT5 is upregulated in PCa, correlates with worse patient survival, promotes corrupted RNA splicing, and functionally cooperates with an array of pro-tumorigenic pathways to enhance oncogenesis. PRMT5 inhibition via either genetic knockdown or pharmacological inhibition reduces stemness with paralleled differentiation and arrests cell cycle progression without causing appreciable Apoptosis. Strikingly, the severity of antitumor effect of PRMT5 inhibition correlates with disease aggressiveness, with AR+ PCa being less affected. Molecular characterization pinpoints MYC, but not (or at least to a lesser degree) AR, as the main partner of PRMT5 to form a positive feedback loop to exacerbate malignancy in both AR+ and AR- PCa cells. Inspired by the surprising finding that PRMT5 negatively correlates with tumor immune infiltration and transcriptionally suppresses an immune-gene program, we further show that although PRMT5 Inhibitor (PRMT5i) EPZ015666 or anti-PD-1 immunotherapy alone exhibits limited antitumor effects, combination of PRMT5i with anti-PD-1 displays superior efficacy in inhibiting castration-resistant PCa (CRPC) in vivo. Finally, to expand the potential use of PRMT5i through a synthetic lethality concept, we also perform a global CRISPR/Cas9 knockout screen to unravel that many clinical-grade drugs of known oncogenic pathways can be repurposed to target CRPC when used in combination with PRMT5i at low doses. Collectively, our findings establish a rationale to exploit PRMT5i in combination with immunotherapy or other targeted therapies to treat aggressive PCa.

Keywords

Cancer stemness; Combination immunotherapy; PRMT5; Prostate cancer.

Figures
Products