Histone Deacetylase Inhibitors (HDACi) Promote KLF5 Ubiquitination and Degradation in Basal-like Breast Cancer

Yanjie Kong^1#, Wenlong Ren^2,8#, Huan Fang^2,3#, Naseer Ali Shah^2#, Yujie Shi⁴, Dingyun You⁵, Chengang Zhou^2,3, Dewei Jiang², Chuanyu Yang², Huichun Liang², Wenjin Liu^2,3, Luzhen Wang^2,8, Wenqiang Gan^2,3, Xing Wan⁶, Fubing Li^2,9✉, Zhen Li^7✉, Ceshi Chen^2✉, Ni Xie^1✉

1. Biobank, The First Affiliated Hospital of Shenzhen University, Shenzhen Second People's Hospital, Shenzhen, 518035, China
2. Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, China
3. Kunming College of Life Sciences, University of Chinese Academy Sciences, Kunming, Yunnan, China
4. Department of Pathology, Henan Provincial People's Hospital, Zhengzhou University, Zhengzhou, Henan, 450003, China
5. Kunming Medical University, Kunming, Yunnan, 650500, China
6. Department of Dermatology, Jingmen No.1 people's Hospital, Jingmen, Hubei, 448000, China
7. Department of the Third Breast Surgery, the Third Affiliated Hospital of Kunming Medical University, Kunming, Yunnan, 650118, China
8. School of Life Science, University of Science & Technology of China. Hefei, Anhui, 230026, China
9. Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, 510095, China
^#These authors contribute equally.

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Citation:
Kong Y, Ren W, Fang H, Shah NA, Shi Y, You D, Zhou C, Jiang D, Yang C, Liang H, Liu W, Wang L, Gan W, Wan X, Li F, Li Z, Chen C, Xie N. Histone Deacetylase Inhibitors (HDACi) Promote KLF5 Ubiquitination and Degradation in Basal-like Breast Cancer. Int J Biol Sci 2022; 18(5):2104-2115. doi:10.7150/ijbs.65322. Available from https://www.ijbs.com/v18p2104.htm

Abstract

Basal-like breast cancer (BLBC) accounts for approximately 15% of all breast cancer cases, and patients with BLBC have a low survival rate. Our previous study demonstrated that the KLF5 transcription factor promotes BLBC cell proliferation and tumor growth. In this study, we demonstrated that the histone deacetylase inhibitors (HDACi), suberoylanilide hydroxamic acid (SAHA), and trichostatin A (TSA), increased KLF5 acetylation at lysine 369 (K369), downregulated KLF5 protein expression levels, and decreased cell viability in BLBC cell lines. HDACi target KLF5 for proteasomal degradation by promoting KLF5 protein ubiquitination. K369 acetylation of KLF5 decreases the binding between KLF5 and its deubiquitinase, BAP1. These findings revealed a novel mechanism by which HDACi suppress BLBC, and a novel crosstalk between KLF5 protein acetylation and ubiquitination.

Keywords: Histone deacetylase, HDAC1, trichostatin A, suberoylanilide hydroxamic acid, basal-like breast cancer, KLF5