CRISPR screening reveals gleason score and castration resistance related oncodriver ring finger protein 19 A (RNF19A) in prostate cancer

Drug Resist Updat. 2023 Mar:67:100912. doi: 10.1016/j.drup.2022.100912. Epub 2023 Jan 3.

Abstract

Prostate cancer (PCa) is one of the most lethal causes of cancer-related death in male. It is characterized by chromosomal instability and disturbed signaling transduction. E3 ubiquitin ligases are well-recognized as mediators leading to genomic alterations and malignant phenotypes. There is a lack of systematic study on novel oncodrivers with genomic and clinical significance in PCa. In this study we used clustered regularly interspaced short palindromic repeats (CRISPR) system to screen 656 E3 ubiquitin ligases as oncodrivers or tumor repressors in PCa cells. We identified 51 significantly changed genes, and conducted genomic and clinical analysis on these genes. It was found that the Ring Finger Protein 19 A (RNF19A) was a novel oncodriver in PCa. RNF19A was frequently amplified and highly expressed in PCa and other cancer types. Clinically, higher RNF19A expression correlated with advanced Gleason Score and predicted castration resistance. Mechanistically, transcriptomics, quantitative and ubiquitination proteomic analysis showed that RNF19A ubiquitylated Thyroid Hormone Receptor Interactor 13 (TRIP13) and was transcriptionally activated by androgen receptor (AR) and Hypoxia Inducible Factor 1 Subunit Alpha (HIF1A). This study uncovers the genomic and clinical significance of a oncodriver RNF19A in PCa. The results of this study indicate that targeting AR/HIF1A-RNF19A-TRIP13 signaling axis could be an alternative option for PCa diagnosis and therapy.

Keywords: Androgen receptor; Castration resistance; Chromosome instability; Gleason Score; Prostate cancer; Ring finger protein 19A.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • ATPases Associated with Diverse Cellular Activities / genetics
  • ATPases Associated with Diverse Cellular Activities / metabolism
  • ATPases Associated with Diverse Cellular Activities / therapeutic use
  • CRISPR-Cas Systems
  • Cell Cycle Proteins / genetics
  • Cell Cycle Proteins / metabolism
  • Cell Line, Tumor
  • Clustered Regularly Interspaced Short Palindromic Repeats
  • Early Detection of Cancer
  • High-Throughput Screening Assays
  • Humans
  • Male
  • Neoplasm Grading
  • Prostatic Neoplasms / genetics
  • Prostatic Neoplasms, Castration-Resistant* / drug therapy
  • Prostatic Neoplasms, Castration-Resistant* / genetics
  • Prostatic Neoplasms, Castration-Resistant* / pathology
  • Proteomics
  • Ubiquitin-Protein Ligases* / genetics
  • Ubiquitins / genetics
  • Ubiquitins / metabolism
  • Ubiquitins / therapeutic use

Substances

  • ATPases Associated with Diverse Cellular Activities
  • Cell Cycle Proteins
  • RNF19A protein, human
  • TRIP13 protein, human
  • Ubiquitin-Protein Ligases
  • Ubiquitins