p63α protein up-regulates heat shock protein 70 expression via E2F1 transcription factor 1, promoting Wasf3/Wave3/MMP9 signaling and bladder cancer invasion

Bladder cancer (BC) is the sixth most common cancer in the United States and is the number one cause of death among patients with urinary system malignancies. This makes the identification of invasive regulator(s)/effector(s) as the potential therapeutic targets for managing BC a high priority. p63 is a member of the p53 family of tumor suppressor genes/proteins, plays a role in the differentiation of epithelial tissues, and is believed to function as a tumor suppressor. However, it remains unclear whether and how p63 functions in BC cell invasion after tumorigenesis. Here, we show that p63 alpha protein levels were much higher in mouse high-invasive BC tissues than in normal tissues. Our results also revealed that p63 alpha is crucial for heat shock protein 70 (Hsp70) expression and subsequently increases the ability of BC invasion. Mechanistic experiments demonstrated that p63 alpha can transcriptionally up-regulate Hsp70 expression, thereby promoting BC cell invasion via the Hsp70/Wasf3/Wave3/MMP-9 axis. Wefurther show that E2F transcription factor 1 (E2F1) mediates p63 alpha overexpressioninduced Hsp70 transcription. We also found that p63 alpha overexpression activates E2F1 transcription, which appears to be stimulated by p63 alpha together with E2F1. Collectively, our results demonstrate that p63 alpha is a positive regulator of BC cell invasion after tumorigenesis, providing significant insights into the biological function of p63 alpha in BC and supporting the notion that p63 alpha might be a potential target for invasive BC therapy.