MiR-100 antagonism triggers apoptosis by inhibiting ubiquitination-mediated p53 degradation.

Abstract

During tumourigenesis, p53 functions as 'the guardian of the genome' because p53-dependent apoptosis strongly regulates the fate of cancer cells. Therefore, p53 regulation must be sensitive and accurate. p53 activity is regulated through its ubiquitination and deubiquitination. However, the role of microRNA in ubiquitin-mediated p53 degradation has not been previously studied. Our previous studies indicated that miR-100 is required for apoptosis. In the current study, the mechanism of p53 protein ubiquitination mediated by miR-100 was characterized. An analysis of primary tumour samples from gastric cancer patients showed a significant correlation between miR-100 upregulation and primary human gastric tumourigenesis and progression. The in vivo and in vitro data indicated that miR-100 antagonism specifically induced the apoptosis of poorly differentiated gastric cancer cells but not non-cancerous gastric cells, indicating that miR-100 has a crucial role in regulating the progression of gastric tumours. In the regulation of p53-dependent apoptosis, miR-100 antagonism inhibited ubiquitin-mediated p53 protein degradation by activating RNF144B, an E3 ubiquitination ligase. Consequently, the miR-100-RNF144B-pirh2-p53-dependent pathway was initiated. Our findings highlight a novel mechanism of ubiquitin-mediated p53 protein degradation in apoptosis.