Inhibition of super enhancer downregulates the expression of KLF5 in basal-like breast cancers

  • Int J Biol Sci. 2019 Jun 10;15(8):1733-1742. doi: 10.7150/ijbs.35138.
Chuan-Huizi Chen  1  2 ,  Nong Yang  3 ,  Yongchang Zhang  3 ,  Jiancheng Ding  4 ,  Wenjuan Zhang  4 ,  Rong Liu  1 ,  Wen Liu  4 ,  Ceshi Chen  1  5  6
Affiliations
  • 1. Key Laboratory of Animal Models and Human Disease Mechanisms of the Chinese Academy of Sciences & Yunnan Province, Kunming Institute of Zoology, Kunming, Yunnan, 650223, China.
  • 2. School of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, China.
  • 3. Department of Medical Oncology, Lung Cancer and Gastrointestinal Unit, Hunan Cancer Hospital/The Affiliated Cancer Hospital of Xiangya School of Medicine, Changsha, Hunan, 410013, China.
  • 4. School of Pharmaceutical Science, Fujian Provincial Key Laboratory of Innovative Drug Target Research, Xiamen University, Xiang'an South Road, Xiamen, Fujian, 361102, China.
  • 5. Institute for Stem Cell and Regeneration, Chinese Academy of Sciences, Beichen West Road, Chaoyang District, Beijing, 100101, China.
  • 6. Affiliated Cancer Hospital & Institute of Guangzhou Medical University, Guangzhou, China, 510095.
PMID: 31360115 DOI: 10.7150/ijbs.35138
Abstract

The transcription factor KLF5 (Krüpple-like factor 5) is highly expressed in basal-like breast Cancer (BLBC), which promotes cell proliferation, survival, migration and stemness, serving as a potential therapeutic target. In the current study, a super-enhancer (SE) was identified to be located downstream of the KLF5 gene in BLBC cell lines, HCC1806 and HCC1937. JQ-1, a BRD4 Inhibitor, inhibits the expression and activity of KLF5 in both HCC1806 and HCC1937 cells in a time- and dose-dependent manner. Compound 870, an in-house BRD4 Inhibitor, exhibited higher potency than JQ-1 to inhibit KLF5 and BLBC growth by arresting cells in G1 phase. Additionally, THZ1, a CDK7 Inhibitor, also inhibits KLF5 and BLBC growth in a similar manner. Our findings suggested that KLF5 is regulated by SE, and modulation of SE could be an effective therapeutic strategy for treating BLBC.

Keywords
BLBC; BRD4; JQ-1; KLF5; Super-enhancer; THZ1.
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