BRD4 REGULATES TRANSCRIPTION FACTOR ∆Np63αTO DRIVE A CANCER STEM CELL PHENOTYPE IN SQUAMOUS CELL CARCINOMAS.

Bromodomain containing protein 4 (BRD4) plays a critical role in controlling the expression of genes involved in development and cancer. Inactivation of BRD4 inhibits cancer growth, making it a promising anticancer drug target. The cancer stem cell population is a key driver of recurrence and metastasis in cancer patients. Here we show that cancer stem-like cells can be enriched from squamous cell carcinomas, and that these cells display an aggressive phenotype with enhanced stem cell marker expression, migration, invasion, and tumor growth. BRD4 was highly elevated in this aggressive subpopulation of cells, and its function is critical for these cancer stem cell-like properties. Moreover, BRD4 regulated ∆Np63α, a key transcription factor that is essential for epithelial stem cell function that is often overexpressed in cancers. BRD4 regulated an EZH2/STAT3 complex that led to increased ∆Np63α-mediated transcription. Targeting BRD4 in human squamous cell carcinoma reduces ∆Np63α, leading to inhibition of spheroid formation, migration, invasion and tumor growth. These studies identify a novel BRD4-regulated signaling network in a subpopulation of cancer stem-like cells elucidating a possible avenue for effective therapeutic intervention.