The heat shock protein 27 (Hsp27) has emerged as a principal factor of the castration-resistant prostate cancer (CRPC) progression. Also, an antisense oligonucleotide (ASO) against Hsp27 (OGX-427 or apatorsen) has been assessed in different clinical trials. Here, we illustrate that Hsp27 highly regulates the expression of the human DEAD-box protein 5 (DDX5), and we define DDX5 as a novel therapeutic target for CRPC treatment. DDX5 overexpression is strongly correlated with aggressive tumor features, notably with CRPC. DDX5 downregulation using a specific ASO-based inhibitor that acts on DDX5 mRNAs inhibits cell proliferation in preclinical models, and it particularly restores the treatment sensitivity of CRPC. Interestingly, through the identification and analysis of DDX5 protein interaction networks, we have identified some specific functions of DDX5 in CRPC that could contribute actively to tumor progression and therapeutic resistance. We first present the interactions of DDX5 and the Ku70/80 heterodimer and the transcription factor IIH, thereby uncovering DDX5 roles in different DNA repair pathways. Collectively, our study highlights critical functions of DDX5 contributing to CRPC progression and provides preclinical proof of concept that a combination of ASO-directed DDX5 inhibition with a DNA damage-inducing therapy can serve as a highly potential novel strategy to treat CRPC.

热休克蛋白 27 (Hsp27) 已成为去势抵抗性前列腺癌 (CRPC) 进展的主要因素。此外，针对 Hsp27（OGX-427 或 apatorsen）的反义寡核苷酸 (ASO) 已在不同的临床试验中进行了评估。在这里，我们说明 Hsp27 高度调节人 DEAD-box 蛋白 5 (DDX5) 的表达，并且我们将 DDX5 定义为 CRPC 治疗的新治疗靶点。 DDX5 过表达与侵袭性肿瘤特征密切相关，特别是与 CRPC。使用作用于 DDX5 mRNA 的特定 ASO 抑制剂下调 DDX5 可抑制临床前模型中的细胞增殖，尤其可以恢复 CRPC 的治疗敏感性。有趣的是，通过鉴定和分析 DDX5 蛋白相互作用网络，我们发现了 DDX5 在 CRPC 中的一些特定功能，这些功能可能对肿瘤进展和治疗耐药做出积极贡献。我们首先介绍了 DDX5 与 Ku70/80 异二聚体和转录因子 IIH 的相互作用，从而揭示了 DDX5 在不同 DNA 修复途径中的作用。总的来说，我们的研究强调了 DDX5 对 CRPC 进展的关键功能，并提供了临床前概念证明，即 ASO 导向的 DDX5 抑制与 DNA 损伤诱导疗法的组合可以作为治疗 CRPC 的一种极具潜力的新策略。