TGF-β causes Docetaxel resistance in Prostate Cancer via the induction of Bcl-2 by acetylated KLF5 and Protein Stabilization

Yixiang Li^1,3, Baotong Zhang^1,3✉, Lingwei Xiang⁴, Siyuan Xia^1,3, Omer Kucuk^1,3, Xingming Deng^2,3, Lawrence H. Boise^1,3, Jin-Tang Dong^1,3✉

1. Department of Hematology and Medical Oncology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
2. Department of Radiation Oncology, Emory University School of Medicine, Atlanta, GA, 30322, USA.
3. Winship Cancer Institute, Emory University, Atlanta, GA, 30322, USA.
4. ICF, Atlanta, GA, 30322, USA.

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Citation:
Li Y, Zhang B, Xiang L, Xia S, Kucuk O, Deng X, Boise LH, Dong JT. TGF-β causes Docetaxel resistance in Prostate Cancer via the induction of Bcl-2 by acetylated KLF5 and Protein Stabilization. Theranostics 2020; 10(17):7656-7670. doi:10.7150/thno.44567. Available from http://www.thno.org/v10p7656.htm

Abstract

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.

Methods: 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.

Results: 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.

Conclusion: 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.

Keywords: KLF5 acetylation, TGF-β, Bcl-2 degradation, prostate cancer, docetaxel resistance