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Theranostics 2019; 9(19):5464-5477. doi:10.7150/thno.33282 This issue Cite

Research Paper

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

Jing Jia^1,2*, Hai-Bao Zhang^1*, Qi Shi¹, Chao Yang¹, Jian-Bin Ma¹, Bin Jin¹, Xinyang Wang^1,3,4, Dalin He^1,3,4✉, Peng Guo^{1,3,4 ✉}

1. Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China, 710061
2. Department of Plastic, Cosmetic and Maxillofacial Surgery, The First Affiliated Hospital of Xi'an Jiaotong University, Xi'an, Shaanxi, China, 710061
3. Key Laboratory for Tumor Precision Medicine of Shaanxi Province, Xi'an, Shaanxi, China, 710061
4. Oncology Research Lab, Key Laboratory of Environment and Genes Related to Diseases, Ministry of Education, Xi'an, Shaanxi, China, 710061
*These two authors contributed equally to this study.

✉ Corresponding author: Peng Guo and Dalin He, Department of Urology, The First Affiliated Hospital of Xi'an Jiaotong University, 277 Yan-Ta West Road, Xi'an, Shaanxi 710061, China. Tel: +86 29 85323661, e-mail: guopeng661xjtu.edu.cn (P. Guo), hedlxjtu.edu.cn (D. He) More

Abstract

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.

Methods: 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 (BECN1) promoter by the ChIP assay, oligonucleotides pulldown, and co-immunoprecipitation. The effect of docetaxel on cell growth in vivo was examined in a CWR22RV1 xenograft tumor mouse model.

Results: 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 in vitro and in vivo, 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.

Conclusions: 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.

Keywords: KLF5, prostate cancer, autophagy, BECN1, docetaxel

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