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.
School of Chinese Materia Medica, Yunnan University of Chinese Medicine, Kunming, Yunnan, 650500, China.
Int J Biol Sci. 2019 Jun 10;15(8):1733-1742. doi: 10.7150/ijbs.35138. eCollection 2019.
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 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.
转录因子 KLF5（Krüpple 样因子 5）在基底样乳腺癌（BLBC）中高度表达，促进细胞增殖、存活、迁移和干性，可作为潜在的治疗靶点。在本研究中，在 BLBC 细胞系 HCC1806 和 HCC1937 中鉴定到一个位于基因下游的超级增强子（SE）。BRD4 抑制剂 JQ-1 以时间和剂量依赖的方式抑制 HCC1806 和 HCC1937 细胞中 KLF5 的表达和活性。一种内部的 BRD4 抑制剂化合物 870 通过将细胞阻滞在 G1 期，比 JQ-1 具有更高的抑制 KLF5 和 BLBC 生长的能力。此外，CDK7 抑制剂 THZ1 也以类似的方式抑制 KLF5 和 BLBC 的生长。我们的研究结果表明，KLF5 受 SE 调控，调节 SE 可能是治疗 BLBC 的有效治疗策略。
