Role of TGF-β and acetylated KLF5 signaling axis in prostate cancer drug resistance Open Access

Li, Yixiang (Fall 2020)

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Prostate cancer is the second leading cause of cancer-related deaths in the United States. Docetaxel (DTX) is the first line treatment for castration resistant prostate cancer; however, almost all patients that receive DTX eventually develop resistance. Utilizing cytotoxicity assays of DTX, Matrigel colony formation assays, mouse xenograft and tibia injection models, we investigated whether TGF-β and acetylated KLF5 affect DTX resistance in prostate cancer. 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. Furthermore, we used two approaches in exploring mechanisms mediating the TGF-β and acetylated KLF5 signaling axis in prostate cancer drug resistance. First, a luciferase reporter system was used to evaluate transcriptional activities. Gene expression was analyzed by RT-qPCR and Western blotting. We showed that the TGF-β/acetylated KLF5 signaling axis activates Bcl-2 expression transcriptionally. DTX-induced Bcl-2 degradation depends on a proteasome pathway, and TGF-β inhibits DTX-induced Bcl-2 ubiquitination. Second, RNA-seq and ChIP-seq modalities were used to determine direct downstream targets of acetylated KLF5. We found CXCR4 could be another promising mediator of acetylated KLF5 induced DTX resistance. Our studies 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.

Table of Contents

Chapter 1: Introduction 8

1.1 Cancer 8

1.2 Prostate cancer 9

1.3 Docetaxel 12

1.4 KLF5 14

1.5 Transforming growth factor-β (TGF-β) 17

1.6 Figures 21

Chapter 2: TGF-β/acetylated KLF5 axis mediates docetaxel drug resistance 26

2.1 Introduction 26

2.2 Material and methods 28

2.3 Results 33

2.4 Discussion 39

2.5 Figures 41

Chapter 3: Mechanisms mediating the TGF-β/acetylated KLF5 induced drug resistance in prostate cancer 48

3.1 Introduction 48

3.2 Material and methods 51

3.3 Results 56

3.4 Discussion 66

3.5 Figures 70

Chapter 4: Discussion 86

4.1 Summary and conclusions 86

4.2 Novel role of TGF-β/Acetylated KLF5 signaling in DTX resistance in prostate cancer 87

4.3 Clinical implications 88

4.4 Future directions 90

4.5 Figures 93

References 97

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