Qin Junying, Zhou Zhongmei, Chen Wenlin, Wang Chunyan, Zhang Hailin, Ge Guangzhe, Shao Ming, You Dingyun, Fan Zhixiang, Xia Houjun, Liu Rong, Chen Ceshi
Key Laboratory of Animal Models and Human Disease Mechanisms of Chinese Academy of Sciences and Yunnan Province, Kunming Institute of Zoology, Chinese Academy of Sciences, Collaborative Innovation Center for Cancer Medicine, Kunming, Yunnan 650223, China.
Graduate School of the Chinese Academy of Sciences, Beijing 100039, China.
Nat Commun. 2015 Sep 30;6:8471. doi: 10.1038/ncomms9471.
The transcription factor KLF5 is highly expressed in basal-like breast cancer and promotes breast cancer cell proliferation, survival, migration and tumour growth. Here we show that, in breast cancer cells, KLF5 is stabilized by the deubiquitinase (DUB) BAP1. With a genome-wide siRNA library screen of DUBs, we identify BAP1 as a bona fide KLF5 DUB. BAP1 interacts directly with KLF5 and stabilizes KLF5 via deubiquitination. KLF5 is in the BAP1/HCF-1 complex, and this newly identified complex promotes cell cycle progression partially by inhibiting p27 gene expression. Furthermore, BAP1 knockdown inhibits tumorigenicity and lung metastasis, which can be rescued partially by ectopic expression of KLF5. Collectively, our findings not only identify BAP1 as the DUB for KLF5, but also reveal a critical mechanism that regulates KLF5 expression in breast cancer. Our findings indicate that BAP1 could be a potential therapeutic target for breast and other cancers.
转录因子KLF5在基底样乳腺癌中高表达，可促进乳腺癌细胞的增殖、存活、迁移及肿瘤生长。在此我们发现，在乳腺癌细胞中，去泛素化酶（DUB）BAP1可使KLF5稳定。通过对DUB进行全基因组siRNA文库筛选，我们确定BAP1为真正的KLF5 DUB。BAP1直接与KLF5相互作用，并通过去泛素化使KLF5稳定。KLF5存在于BAP1/HCF-1复合物中，这个新发现的复合物部分通过抑制p27基因表达促进细胞周期进程。此外，敲低BAP1可抑制肿瘤发生及肺转移，而异位表达KLF5可部分挽救这种抑制作用。总的来说，我们的研究结果不仅确定了BAP1为KLF5的DUB，还揭示了乳腺癌中调节KLF5表达的关键机制。我们的研究结果表明，BAP1可能是乳腺癌及其他癌症的潜在治疗靶点。
