TRIM17 downregulation modulates CRPC progression and enzalutamide resistance by derepressing BCL2 expression via the p53-dependent and p53-independent pathways

  • Cell Death Differ. 2026 Jun 13. doi: 10.1038/s41418-026-01778-7.
Zhi Shang  #  1 ,  Guowen Lin  #  1 ,  Liu Yu  #  1 ,  Shiwei Liu  1 ,  Yongqing Zhang  1 ,  Shengfeng Zheng  1 ,  Zongyuan Hong  2 ,  Zhe Hong  3 ,  Dingwei Ye  4
Affiliations
  • 1. Department of Urology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University; Shanghai Genitourinary Cancer Institute, Shanghai, China.
  • 2. Department of Pharmacology and Laboratory of Quantitative Pharmacology, Wannan Medical College, Wuhu, China. [email protected].
  • 3. Department of Urology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University; Shanghai Genitourinary Cancer Institute, Shanghai, China. [email protected].
  • 4. Department of Urology, Fudan University Shanghai Cancer Center; Department of Oncology, Shanghai Medical College, Fudan University; Shanghai Genitourinary Cancer Institute, Shanghai, China. [email protected].
  • # Contributed equally.
PMID: 42288623 DOI: 10.1038/s41418-026-01778-7
Abstract

The failure of second-generation antiandrogen drugs such as enzalutamide (ENZ) treatment indicates that prostate Cancer (PCa) can progress to castration-resistant prostate Cancer (CRPC). CRPC is considered the terminal stage of PCa and currently has no effective treatment options due to drug resistance. However, the underlying mechanism of ENZ- resistance in CRPC remains unclear. Here, we conducted a single-cell transcriptomic analysis in combination with a gene module clustering assessment to identify the regulatory genes enriched along the hormone-sensitive PCa and CRPC trajectories. This approach revealed that tripartite motif-containing 17 (TRIM17) is a specific time-dependent gene and key regulator that is expressed at significantly low levels in CRPC cells but at high levels in nonresistant epithelial PCa cells. Analysis of patient-derived clinical specimens and in vitro functional experiments demonstrated that TRIM17 low expression could promote CRPC progression and ENZ resistance. Moreover, TRIM17 activation markedly inhibited CRPC progression and enhanced the sensitivity of CRPC cells to ENZ. Mechanistically, TRIM17 binds to and ubiquitinates B-cell lymphoma-2 (BCL2) directly to mediate its degradation. On the Other hand, TRIM17 represses BCL2 by inhibiting p53 degradation by TRIM28. The stabilization of p53 suppresses BCL2 expression and interferes with the abundance and signaling of BCL2 in CRPC cells, further inhibiting CRPC progression and conveying ENZ resensitivity. Importantly, the TRIM17 activator pioglitazone, a registered drug for type 2 diabetes, could synergize with ENZ to reverse ENZ resistance and amplify its cytotoxic effects on CRPC cells. In conclusion, this study identifies a previously undefined function of TRIM17 to modulate ENZ sensitivity and reveals that activation of TRIM17 has great potential as a promising therapeutic strategy for ENZ- resistant PCa, indicating that TRIM17 can serve as a biomarker to guide the treatment of CRPC.

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