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

Abstract

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 p63α protein levels were much higher in mouse high-invasive BC tissues than in normal tissues. Our results also revealed that p63α is crucial for heat shock protein 70 (Hsp70) expression and subsequently increases the ability of BC invasion. Mechanistic experiments demonstrated that p63α can transcriptionally up-regulate Hsp70 expression, thereby promoting BC cell invasion via the Hsp70/Wasf3/Wave3/MMP-9 axis. We further show that E2F transcription factor 1 (E2F1) mediates p63α overexpression-induced Hsp70 transcription. We also found that p63α overexpression activates E2F1 transcription, which appears to be stimulated by p63α together with E2F1. Collectively, our results demonstrate that p63α is a positive regulator of BC cell invasion after tumorigenesis, providing significant insights into the biological function of p63α in BC and supporting the notion that p63α might be a potential target for invasive BC therapy.

• Authors: Honglei Jin, Qipeng Xie, Xirui Guo, Jiheng Xu, Annette Wang, Jingxia Li, Junlan Zhu, Xue-Ru Wu, Haishan Huang, Chuanshu Huang
• Journal: The Journal of biological chemistry (J Biol Chem) Vol. 292 Issue 38 Pg. 15952-15963 (09 22 2017) ISSN: 1083-351X [Electronic] United States
• PMID: 28794159 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't)

Chemical References

• E2F1 Transcription Factor
• HSP70 Heat-Shock Proteins
• Sp1 Transcription Factor
• TP63 protein, human
• Transcription Factors
• Tumor Suppressor Proteins
• Wiskott-Aldrich Syndrome Protein Family
• Matrix Metalloproteinase 9

Topics

• Animals
• Cell Line, Tumor
• Cell Proliferation
• E2F1 Transcription Factor (genetics, metabolism)
• HSP70 Heat-Shock Proteins (genetics, metabolism)
• Humans
• Male
• Matrix Metalloproteinase 9 (metabolism)
• Mice
• Neoplasm Invasiveness
• Signal Transduction
• Sp1 Transcription Factor (metabolism)
• Transcription Factors (metabolism)
• Transcription, Genetic
• Tumor Suppressor Proteins (metabolism)
• Up-Regulation
• Urinary Bladder Neoplasms (genetics, metabolism, pathology)
• Wiskott-Aldrich Syndrome Protein Family (metabolism)