Abstract LB-120: Acetylated Kruppel-like factor 5 and transforming growth factor-β mediated drug resistance in prostate cancer

Abstract

Abstract Purpose: In this study, we explored the role of Kruppel-like factor 5 (KLF5) and its acetylated form on lysine 369 in transforming growth factor-β (TGFβ) induced drug resistance to promote antitumor synergy and overcome drug resistance in advanced stage prostate cancer. Procedures: Two aggressive prostate cancer cell lines DU 145 and PC-3 were treated with docetaxel to measure cytotoxicity. To assess docetaxel resistance, we used in-vitro cell survival assay, colony survival assay and xenograft mouse model. In addition, TGFβ1 and SB505124 (TGFβ receptor I inhibitor) were used to explore TGFβ induced docetaxel resistance. To measure function of KLF5 and its different acetylation form on lysine 369, stable cell lines were constructed with different KLF5 acetylation status mimics after knocking out endogenous KLF5, utilizing the CRISPR-Cas9 system. Results: We found that KLF5 alone induced docetaxel resistance in vivo, but not in vitro. Moreover, endogenous knocking out of KLF5 inhibited TGFβ induced docetaxel resistance. In addition to previous findings that TGFβ recruits P300 acetyl-transferase to acetylate KLF5 on lysine 369, we further found that TGFβ induced docetaxel resistance depends on acetylation of KLF5. In addition, Mass Spectrometry analysis revealed that JUNB, a downstream target of non-canonical TGFβ pathway, is a direct binding target of acetylated KLF5 but not de-acetylated KLF5. Knocking down of JUNB in acetylated KLF5 mimic cell line inhibited TGFβ induced docetaxel resistance. Conclusions: These suggested that acetylated KLF5 is indispensable in TGFβ induced drug resistance through interaction with JUNB. Our study introduced a novel mechanism of acetylated KLF5 and JUNB mediated docetaxel resistance in prostate cancer and contributed to an advanced therapy combination for advanced prostate cancer patients. Citation Format: Yixiang Li, Baotong Zhang, Jin-Tang Dong. Acetylated Kruppel-like factor 5 and transforming growth factor-β mediated drug resistance in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-120.