HDAC-mediated deacetylation of KLF5 associates with its proteasomal degradation

• Type of Material: Article
• Authors: Ran Tao, Emory University; Baotong Zhang, Emory University; Yixiang Li, Emory University; Jamie L. King, Emory University; Ruoyu Tian, Nankai University; Siyuan Xia, Emory University; Cara Rae Schiavon, Emory University; Jin-Tang Dong, Emory University
• Language: English
• Date: 2018-06-07
• Publisher: Elsevier: 12 months
• Publication Version: Author Accepted Manuscript (After Peer Review)
• Copyright Statement: © 2019 Elsevier B.V. or its licensors or contributors
• License: Creative Commons Attribution-NonCommercial-NoDerivs 4.0 International
• Final Published Version (URL): http://dx.doi.org/10.1016/j.bbrc.2018.04.153
• Title of Journal or Parent Work: Biochemical and Biophysical Research Communications
• ISSN: 0006-291X
• Volume: 500
• Issue: 3
• Start Page: 777
• End Page: 782
• Grant/Funding Information: This work was supported by grant R01CA171189 from the National Cancer Institute; National Institutes of Health; and grant 81130044 from the National Natural Science Foundation of China.
• Keywords: REGULATOR; Science & Technology; KLF5; P21; TRANSCRIPTION FACTOR; Histone deacetylases (HDACs); PROSTATE-CANCER; Life Sciences & Biomedicine; TARGET; ACETYLATION; Biophysics; Protein stability; STEM-LIKE CELLS; EXPRESSION; EPITHELIAL-CELLS; Acetylation; Biochemistry & Molecular Biology; KRUPPEL-LIKE FACTOR-5
• Research Categories: Biology, Cell; Health Sciences, Oncology; Chemistry, Biochemistry

Abstract

Krüppel-like factor 5 (KLF5) is a basic transcription factor that regulates diverse cellular processes during tumor development. Acetylation of KLF5 at lysine 369 (K369) reverses its function from promoting to suppressing cell proliferation and tumor growth. In this study, we examined the regulation of KLF5 by histone deacetylases in the prostate cancer cell line DU 145. While confirming the functions of HDAC1/2 in KLF5 deacetylation and the promotion of cell proliferation, we found that the knockdown of HDAC1/2 upregulated KLF5 protein but not KLF5 mRNA, and the increase in KLF5 protein level by silencing HDAC1/2 was at least in part due to decreased proteasomal degradation. Deacetylase activity was required for HDAC1/2-mediated KLF5 degradation, and mutation of KLF5 to an acetylation-mimicking form prevented its degradation, even though the mutation did not affect the binding of KLF5 with HDAC1/2. Mutation of K369 to arginine, which prevents acetylation, did not affect the binding of KLF5 to HDAC1 or the response of KLF5 to HDAC1/2-promoted degradation. These findings provide a novel mechanistic association between the acetylation status of KLF5 and its protein stability. They also suggest that maintaining KLF5 in a deacetylated form may be an important mechanism by which KLF5 and HDACs promote cell proliferation and tumor growth.