TRIM17下调通过p53依赖性和p53非依赖性途径降低BCL2表达，调节CRPC进展和恩杂鲁胺耐药性
TRIM17 downregulation modulates CRPC progression and enzalutamide resistance by derepressing BCL2 expression via the p53-dependent and p53-independent pathways.
摘要(中文译文)
第二代抗雄激素药物如恩杂鲁胺（enzalutamide，ENZ）治疗的失败表明，前列腺癌（prostate cancer，PCa）可进展为去势抵抗性前列腺癌（castration-resistant prostate cancer，CRPC）。CRPC被认为是前列腺癌的终末期，由于耐药性目前尚无有效的治疗选择。然而，CRPC中ENZ耐药的潜在机制仍不清楚。在此，我们进行了单细胞转录组分析，结合基因模块聚类评估，以鉴定沿激素敏感性前列腺癌和CRPC轨迹富集的调控基因。该方法揭示了含三联基序蛋白17（tripartite motif-containing 17，TRIM17）是一个特定的时间依赖性基因和关键调控因子，其在CRPC细胞中表达水平显著降低，而在非耐药上皮性前列腺癌细胞中表达水平较高。患者来源的临床标本分析和体外功能实验表明，TRIM17低表达可促进CRPC进展和ENZ耐药。此外，TRIM17激活显著抑制CRPC进展并增强CRPC细胞对ENZ的敏感性。在机制上，TRIM17直接结合B细胞淋巴瘤-2（B-cell lymphoma-2，BCL2）并使其泛素化，从而介导其降解。另一方面，TRIM17通过抑制TRIM28对p53的降解来抑制BCL2。p53的稳定化抑制BCL2表达，并干扰CRPC细胞中BCL2的丰度和信号传导，进一步抑制CRPC进展并恢复对ENZ的敏感性。重要的是，TRIM17激活剂吡格列酮（pioglitazone），一种已注册的2型糖尿病治疗药物，可与ENZ协同逆转ENZ耐药并放大其对CRPC细胞的细胞毒性作用。总之，本研究鉴定了TRIM17调节ENZ敏感性的一个此前未定义的功能，并揭示了激活TRIM17作为一种有前景的ENZ耐药前列腺癌治疗策略具有巨大潜力，表明TRIM17可作为指导CRPC治疗的生物标志物。
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.
如何引用
AMA
Zhi Shang, Guowen Lin, Liu Yu, Shiwei Liu, Yongqing Zhang, Shengfeng Zheng, et al. TRIM17 downregulation modulates CRPC progression and enzalutamide resistance by derepressing BCL2 expression via the p53-dependent and p53-independent pathways.. Cell death and differentiation. 2026; doi:10.1038/s41418-026-01778-7.
APA
Zhi Shang, Guowen Lin, Liu Yu, Shiwei Liu, Yongqing Zhang, Shengfeng Zheng, et al (2026). TRIM17 downregulation modulates CRPC progression and enzalutamide resistance by derepressing BCL2 expression via the p53-dependent and p53-independent pathways.. Cell death and differentiation. https://doi.org/10.1038/s41418-026-01778-7
GB/T 7714
Zhi Shang, Guowen Lin, Liu Yu, Shiwei Liu, Yongqing Zhang, Shengfeng Zheng, et al. TRIM17 downregulation modulates CRPC progression and enzalutamide resistance by derepressing BCL2 expression via the p53-dependent and p53-independent pathways.[J]. Cell death and differentiation, 2026 doi:10.1038/s41418-026-01778-7.
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