Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China, 710061.
Department of Plastic, Cosmetic and Maxillofacial Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China, 710061.
Theranostics. 2019 Jul 28;9(19):5464-5477. doi: 10.7150/thno.33282. eCollection 2019.
KLF5 is frequently deleted or downregulated in prostate cancer. However, it is not known whether downregulation of KLF5 is associated with the response of prostate cancer cells to chemotherapy and/or prognosis of patients. We monitored cell growth by MTT and colony formation assays, and cell autophagy through tandem fluorescence microscopy and transmission electron microscopy. Gene expression was analyzed by RT-qPCR and Western blotting. We determined the binding of KLF5 together with HDAC3 on the beclin-1 () promoter by the ChIP assay, oligonucleotides pulldown, and co-immunoprecipitation. The effect of docetaxel on cell growth was examined in a CWR22RV1 xenograft tumor mouse model. : In the present study, we found that KLF5 down-regulation was associated with progression of prostate cancer and poor prognosis of patients. KLF5 knockdown reduced the sensitivity of prostate cancer cells to docetaxel and , and docetaxel treatment decreased the expression of KLF5. Moreover, we confirmed that docetaxel treatment inhibited cell death by inducing autophagy in prostate cancer cells. Thus, we hypothesized that KLF5 could be a regulator of cell autophagy. Interestingly, KLF5 could inhibit prostate cancer cell autophagy by suppressing the transcription of BECN1 cooperatively with HDAC3. Another significant finding was that docetaxel treatment repressed KLF5 expression through AMPK/mTOR/p70S6K signaling pathway resulting in increased BECN1, induction of cell autophagy, and promotion of cell survival in castration-resistant prostate cancer cells. Our results indicated that downregulation of KLF5 promoted cell autophagy in prostate cancer. Furthermore, reduced KLF5 also facilitated cell autophagy induced by docetaxel resulting in desensitization to the drug and cell survival. Decreased levels of KLF5 led to increased BECN1 via AMPK/mTOR/p70S6K signaling. Thus, repression of BECN1 and cell autophagy was critical for KLF5 to increase the sensitivity of prostate cancer cells to docetaxel.
KLF5 在前列腺癌中经常缺失或下调。然而，尚不清楚 KLF5 的下调是否与前列腺癌细胞对化疗的反应和/或患者的预后有关。我们通过 MTT 和集落形成测定监测细胞生长，通过串联荧光显微镜和透射电子显微镜监测细胞自噬。通过 RT-qPCR 和 Western blot 分析基因表达。我们通过 ChIP 测定、寡核苷酸下拉和共免疫沉淀来确定 KLF5 与 HDAC3 一起结合在 beclin-1 ()启动子上。我们在 CWR22RV1 异种移植肿瘤小鼠模型中检查了多西紫杉醇对细胞生长的影响。：在本研究中，我们发现 KLF5 的下调与前列腺癌的进展和患者的不良预后有关。KLF5 敲低降低了前列腺癌细胞对多西紫杉醇的敏感性和，多西紫杉醇处理降低了 KLF5 的表达。此外，我们证实多西紫杉醇处理通过诱导前列腺癌细胞自噬来抑制细胞死亡。因此，我们假设 KLF5 可以作为细胞自噬的调节剂。有趣的是，KLF5 可以通过与 HDAC3 协同抑制 BECN1 的转录来抑制前列腺癌细胞自噬。另一个重要发现是，多西紫杉醇处理通过 AMPK/mTOR/p70S6K 信号通路抑制 KLF5 表达，导致 BECN1 增加，诱导细胞自噬，并促进去势抵抗性前列腺癌细胞的存活。我们的结果表明，KLF5 的下调促进了前列腺癌中的细胞自噬。此外，KLF5 的减少还促进了多西紫杉醇诱导的细胞自噬，从而使药物脱敏和细胞存活。KLF5 水平降低导致通过 AMPK/mTOR/p70S6K 信号增加 BECN1。因此，抑制 BECN1 和细胞自噬对于 KLF5 增加前列腺癌细胞对多西紫杉醇的敏感性至关重要。
