Pan-Cancer Biomarker miR-151a Regulates p21 Partially Through p53

Abstract

Dysregulation of microRNAs (miRNAs) has been associated with a variety of cancers. We previously identified miR-151a as a potential cell fitness-regulating microRNA using a miRNA-targeted CRISPR-Cas9 genetic screen. In this study, we created mutant cell clones with loss of miR-151a expression and verified miR-151a mutations indeed decreased cell growth. In miR-151a mutant cells, there was an increase in the fraction of cells in the G1-phase of the cell cycle. This increase in G1 cells corresponded to an increase in p53 (TP53) and p21 (CDKN1A) protein levels. Both strands of miR-151a could suppress p53; miR-151a-3p was able to directly suppress p53 expression, but the miR-151a-5p suppression of p53 apparently was indirect. Re-expression of miR-151a-5p in the mutant cells significantly decreased the p53 and p21 protein levels as well as the percentage of cells in G1, while re-expression of miR-151a-3p ironically had a modest effect. These results suggest that both the 5p and 3p strands as well as additional factors are involved in the regulation of p53/p21 and the cell cycle by miR-151a. We also analyzed the TCGA database and discovered that increased miR-151a expression occurs in many tumor types; furthermore, there was an inverse correlation between miR-151a and p21 expression, and high miR-151a expression was often associated with poor overall survival. Taken together, results from this study identify a previously underappreciated role of miR-151a in cancer through regulation of the cell cycle, and they also suggest inhibiting the less abundant 5p may be more important than inhibiting the more abundant 3p of miR-151a for therapeutic considerations.