microRNA-141 regulates BMI1 expression and induces senescence in human diploid fibroblasts

Polycomb group protein BMIl is an important regulator of senescence, aging, and cancer. On one hand, it is overexpressed in cancer cells and is required for self-renewal of stem cells. On the other hand, it is downregulated during senescence and aging. MicroRNAs have emerged as major regulators of almost every gene associated with cancer, aging, and related pathologies. At present, very little is known about the miRNAs that regulate the expression of BMIl. Here, we report that miR-141 posttranscriptionally downregulates BMI1 expression in human diploid fibroblasts (HDFs) via a miR141 targeting sequence in the 3' untranslated region of BMIl mRNA. We also show that overexpression of miR-141 induces premature senescence in HDFs via targeting of BMII in normal but not in exogenous BM11-overexpressing HDFs. Induction of premature senescence in HDFs was accompanied by upregulation of p16INK4a, an important downstream target of BMI1 and a major regulator of senescence. Our results suggest that miR-141-based therapies could be developed to treat pathologies where BMIl is deregulated.