Decreased c-Myc mRNA Stability via the MicroRNA 141-3p/AUF1 Axis Is Crucial for p63α Inhibition of Cyclin D1 Gene Transcription and Bladder Cancer Cell Tumorigenicity

Abstract

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 p63α protein translation and enhancing normal urothelial transformation, whereas p63α 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 p63α inhibited cyclin D1 protein expression, subsequently decreasing the ability of BC cell anchorage-independent growth and tumorigenicity Mechanistic studies demonstrated that p63α 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 p63α directly releases its inhibition of 3' untranslated region (UTR) activity of AU-rich 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 p63α 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 p63α in regulation of BC cell tumorigenic growth and progression/invasion.

CDCA7L promotes glioma proliferation by targeting CCND1 and predicts an unfavorable prognosis

“…As a target gene of c-Myc, CDCA7L can interact with c-Myc, and c-Myc has been found in multiple studies to be closely related to cyclin D1 in a variety of tumors (14–16). Moreover, previous studies have proven that CDCA7L can regulate the cell cycle, and that CCND1 may be an important target gene of CDCA7L in hepatocellular carcinoma (HCC) (8).…”

MicroRNA-141 suppresses growth and metastatic potential of head and neck squamous cell carcinoma

“…In many tumors, levels of miR-141 expression are lower than in healthy tissue, and its increased expression can inhibit tumor progression [11]. For example, miR-141 has been shown to inhibit the development of gastric, prostate, colorectal and liver cancers by inhibiting cell proliferation and metastasis and promoting cell apoptosis [12–14].…”

The Role of Noncoding RNAs in the Regulation of Anoikis and Anchorage-Independent Growth in Cancer

“…In addition to the regulation of KLF12 by miR-141-3p ( Section 2.1.2 ), this miRNA also targets AU-rich element RNA-binding protein 1 (AUF1, also named HNRNPD) [ 35 ], which can decay CCND1 mRNAs [ 82 ]. Additional evidence showed that miR-141-3p expression is repressed by tumor protein P63 alpha containing the transactivation domain (TAp63α), leading to a reduction of CCND1.…”

“…Additional evidence showed that miR-141-3p expression is repressed by tumor protein P63 alpha containing the transactivation domain (TAp63α), leading to a reduction of CCND1. Besides, TAp63α diminishes in vitro anchorage-independent growth and in vivo tumorigenic growth of bladder cancer [ 35 ]. TAp63α and CCND1 are considered to suppress metastasis and anoikis, respectively [ 9 , 83 , 84 ].…”