Decreased c-Myc mRNA Stability via the MicroRNA 141-3p/AUF1 Axis Is Crucial for p63 alpha Inhibition of Cyclin D1 Gene Transcription and Bladder Cancer Cell Tumorigenicity

Bladder cancer (BC) ranks as the sixth most common cancer in the United States and is the leading cause of death in patients with urinary malignancies. p63 is a member of the p53 family and is believed to function as a tumor suppressor in human BCs. Our most recent studies revealed a previously unknown function of the RING of XIAP in promoting microRNA 4295 (miR-4295) transcription, thereby reducing p63 alpha protein translation and enhancing normal urothelial transformation, whereas p63 alpha upregulates hsp70 transcription, subsequently activating the HSP70/Wasf3/Wave3/matrix metalloproteinase 9 (MMP-9) axis and promoting BC cell invasion via initiating the transcription factor E2F1. In this study, we found that p63 alpha inhibited cyclin D1 protein expression, subsequently decreasing the ability of BC cell anchorage-independent growth in vitro and tumorigenicity in vivo. Mechanistic studies demonstrated that p63 alpha expression is able to downregulate cyclin D1 gene transcription through attenuation of c-Myc mRNA stability. We further show that the reduction of miR-141-3p expression by p63 alpha directly releases its inhibition of 3' untranslated region (UTR) activity of AUrich element RNA-binding factor 1 (AUF1) mRNA, thereby increasing AUF1 protein translation and further resulting in degradation of c-Myc mRNA, which, in turn, reduces cyclin D1 gene transcription and BC cell anchorage-independent growth. Collectively, our results demonstrate that p63 alpha is a negative regulator of BC cell tumorigenic growth, a distinctly different function than its promotion of BC invasion, thus providing further new insight into the two faces of p63 alpha in regulation of BC cell tumorigenic growth and progression/invasion.