Prostate cancer is the second leading cause of cancer-related death in the United States. As a first line treatment for hormone-refractory prostate cancer, docetaxel (DTX) treatment leads to suboptimal effect since almost all patients eventually develop DTX resistance. In this study, we investigated whether and how TGF-β affects DTX resistance of prostate cancer./nMethods: Cytotoxicity of DTX in DU 145 and PC-3 cells was measured by CCK-8 and Matrigel colony formation assays. Resistance to DTX in DU 145 cells was examined in a xenograft tumorigenesis model. A luciferase reporter system was used to determine transcriptional activities. Gene expression was analyzed by RT-qPCR and Western blotting./nResults: We found that KLF5 is indispensable in TGF-β-induced DTX resistance. Moreover, KLF5 acetylation at lysine 369 mediates DTX resistance in vitro and in vivo. We showed that the TGF-β/acetylated KLF5 signaling axis activates Bcl-2 expression transcriptionally. Furthermore, DTX-induced Bcl-2 degradation depends on a proteasome pathway, and TGF-β inhibits DTX-induced Bcl-2 ubiquitination./nConclusion: Our study demonstrated that the TGF-β-acetylated KLF5-Bcl-2 signaling axis mediates DTX resistance in prostate cancer and blockade of this pathway could provide clinical insights into chemoresistance of prostate cancer.

中文翻译：

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TGF-β通过乙酰化KLF5和蛋白稳定作用诱导Bcl-2引起前列腺癌多西他赛耐药。

在美国，前列腺癌是癌症相关死亡的第二大主要原因。作为激素难治性前列腺癌的一线治疗方法，多西他赛（DTX）治疗导致效果欠佳，因为几乎所有患者最终都会产生DTX耐药性。在这项研究中，我们研究了TGF-β是否以及如何影响前列腺癌的DTX耐药性。/n方法：通过CCK-8和Matrigel集落形成测定法，测定DU 145和PC-3细胞中DTX的细胞毒性。在异种移植肿瘤发生模型中检查了DU 145细胞对DTX的抗性。萤光素酶报道系统用于确定转录活性。通过RT-qPCR和蛋白质印迹分析基因表达。/n结果：我们发现KLF5在TGF-β诱导的DTX抗性中是必不可少的。此外，赖氨酸369处的KLF5乙酰化在体外和体内介导DTX抗性。我们表明TGF-β/乙酰化的KLF5信号转导轴转录激活Bcl-2表达。此外，DTX诱导的Bcl-2的降解依赖于蛋白酶体途径，以及TGF-β抑制DTX诱导的Bcl-2的ubiquitination./n结论：我们的研究表明，TGF-β乙酰化KLF5-Bcl-2的信号轴介导前列腺癌中的DTX耐药性和对此途径的阻断可为前列腺癌的化学耐药性提供临床见解。