Cellular senescence mediated by p16INK4A-coupled miRNA pathways

• Published in: Nucleic acids research 2014-02, Vol.42 (3), p.1606-1618
• Main Authors: Overhoff, Marita G, Garbe, James C, Koh, James, Stampfer, Martha R, Beach, David H, Bishop, Cleo L
• Format: Article
• Language: English
• Subjects: BASIC BIOLOGICAL SCIENCES; Biochemistry & Molecular Biology; Cells, Cultured; Cellular Senescence - genetics; Cyclin-Dependent Kinase Inhibitor p16 - metabolism; Epigenesis, Genetic; Feedback, Physiological; Fibroblasts - cytology; Fibroblasts - metabolism; Gene Regulation, Chromatin and Epigenetics; Gene Silencing; Humans; MicroRNAs - metabolism; Polycomb-Group Proteins - genetics; Polycomb-Group Proteins - metabolism; Young Adult
• ISSN: 0305-1048; 1362-4962
• DOI: 10.1093/nar/gkt1096

p16 is a key regulator of cellular senescence, yet the drivers of this stable state of proliferative arrest are not well understood. Here, we identify 22 senescence-associated microRNAs (SA-miRNAs) in normal human mammary epithelial cells. We show that SA-miRNAs-26b, 181a, 210 and 424 function in concert to directly repress expression of Polycomb group (PcG) proteins CBX7, embryonic ectoderm development (EED), enhancer of zeste homologue 2 (EZH2) and suppressor of zeste 12 homologue (Suz12), thereby activating p16. We demonstrate the existence of a tight positive feedback loop in which SA-miRNAs activate and re-enforce the expression of other SA-miRNA members. In contrast, PcG members restrain senescence by epigenetically repressing the expression of these SA-miRNAs. Importantly, loss of p16 leads to repression of SA-miRNA expression, intimately coupling this effector of senescence to the SA-miRNA/PcG self-regulatory loop. Taken together, our findings illuminate an important regulatory axis that underpins the transition from proliferation to cellular senescence.