KLF5 downregulation desensitizes castration-resistant prostate cancer cells to docetaxel by increasing BECN1 expression and inducing cell autophagy

• Published in: Theranostics Vol. 9; no. 19; pp. 5464 - 5477
• Main Authors: Jia, Jing, Zhang, Hai-Bao, Shi, Qi, Yang, Chao, Ma, Jian-Bin, Jin, Bin, Wang, Xinyang, He, Dalin, Guo, Peng
• Format: Journal Article
• Language: English
• Published: Australia Ivyspring International Publisher Pty Ltd 01.01.2019; Ivyspring International Publisher
• Subjects: Animals; Antibodies; Autophagy; Autophagy - drug effects; Beclin-1 - genetics; Beclin-1 - metabolism; Cancer therapies; Cell Line, Tumor; Chemotherapy; Docetaxel - administration & dosage; Down-Regulation - drug effects; Drug Resistance, Neoplasm; Gene Expression Regulation, Neoplastic - drug effects; Humans; Kruppel-Like Transcription Factors - genetics; Kruppel-Like Transcription Factors - metabolism; Male; Medical prognosis; Mice; Microscopy; Phosphatase; Plasmids; Prostate cancer; Prostatic Neoplasms, Castration-Resistant - drug therapy; Prostatic Neoplasms, Castration-Resistant - genetics; Prostatic Neoplasms, Castration-Resistant - metabolism; Prostatic Neoplasms, Castration-Resistant - physiopathology; Proteins; Reagents; Research Paper; Tumors; United States > US; China; Germany; BECN1; prostate cancer; KLF5; autophagy; docetaxel
• ISSN: 1838-7640; 1838-7640
• DOI: 10.7150/thno.33282

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.