JOURNAL ARTICLE

Disrupting the interaction of BRD4 with diacetylated Twist suppresses tumorigenesis in basal-like breast cancer

Jian Shi, Yifan Wang, Lei Zeng, Yadi Wu, Jiong Deng, Qiang Zhang, Yiwei Lin, Junlin Li, Tiebang Kang, Min Tao, Elena Rusinova, Guangtao Zhang, Chi Wang, Haining Zhu, Jun Yao, Yi-Xin Zeng, B Mark Evers, Ming-Ming Zhou, Binhua P Zhou
Cancer Cell 2014 February 10, 25 (2): 210-25
24525235
Twist is a key transcription activator of epithelial-mesenchymal transition (EMT). It remains unclear how Twist induces gene expression. Here we report a mechanism by which Twist recruits BRD4 to direct WNT5A expression in basal-like breast cancer (BLBC). Twist contains a "histone H4-mimic" GK-X-GK motif that is diacetylated by Tip60. The diacetylated Twist binds the second bromodomain of BRD4, whose first bromodomain interacts with acetylated H4, thereby constructing an activated Twist/BRD4/P-TEFb/RNA-Pol II complex at the WNT5A promoter and enhancer. Pharmacologic inhibition of the Twist-BRD4 association reduced WNT5A expression and suppressed invasion, cancer stem cell (CSC)-like properties, and tumorigenicity of BLBC cells. Our study indicates that the interaction with BRD4 is critical for the oncogenic function of Twist in BLBC.

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