p16INK4Ainduces senescence and inhibits EMT through microRNA-141/microRNA-146b-5p-dependent repression of AUF1.
Senescence and epithelial-to-mesenchymal transition (EMT) processes are under the control of common tumor suppressor proteins, EMT transcription factors, and microRNAs. However, the molecular mechanisms that coordinate the functional link between senescence and EMT are still elusive. We have shown here that p16INK4A-related induction of senescence is mediated through miR-141 and miR-146b-5p. These two microRNAs are up-regulated in aging human fibroblast and epithelial cells. Furthermore, miR-141 and miR146b-5p trigger cell cycle arrest at G1 phase and induce senescence in primary human fibroblasts and breast cancer cells in the presence and absence of p16INK4A. Like p16INK4A-induced senescence, miR-141/miR146b-5p-related senescence is not associated with secretory phenotype, and is mediated through the RNA binding protein AUF1. We have further demonstrated that p16INK4Aand its downstream miRNA targets inhibit EMT through suppressing the EMT inducer ZEB1 in an AUF1-dependent manner. Indeed, AUF1 binds the mRNA of this gene leading to increase in its level. These results indicate that p16INK4Acontrols both senescence and EMT through repressing EMT-related transcription factor via miR-141/miR146b-5p and their target AUF1. This sheds more light on the molecular basis of the tumor suppressive functions of p16INK4A, which represses both the proliferative and the migratory/invasive capacities of cells. © 2016 Wiley Periodicals, Inc.
The National Center for Genomics Research, King Abdulaziz City for Science and Technology, Riyadh, Saudi Arabia.|Department of Molecular Oncology, King Faisal Specialist Hospital Research Center, Riyadh, Saudi Arabia.
Huda H
HH
Al-Khalaf
Department of Molecular Oncology, King Faisal Specialist Hospital Research Center, Riyadh, Saudi Arabia.
Abdelilah
A
Aboussekhra
D002453:Cell Cycle; D045744:Cell Line, Tumor; D002465:Cell Movement; D049109:Cell Proliferation; D002470:Cell Survival; D016922:Cellular Senescence; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18 / Q000235:genetics* / Q000378:metabolism; D004847:Epithelial Cells / Q000166:cytology* / Q000378:metabolism; D058750:Epithelial-Mesenchymal Transition; D005347:Fibroblasts / Q000166:cytology* / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D / Q000235:genetics* / Q000378:metabolism; D006801:Humans; D035683:MicroRNAs / Q000235:genetics*; D015854:Up-Regulation
C000614131:CDKN2A protein, human; D019941:Cyclin-Dependent Kinase Inhibitor p16; D050763:Cyclin-Dependent Kinase Inhibitor p18; C000630986:HNRNPD protein, human; D000081035:Heterogeneous Nuclear Ribonucleoprotein D0; D034502:Heterogeneous-Nuclear Ribonucleoprotein D; C533895:MIRN141 microRNA, human; C542542:MIRN146 microRNA, human; D035683:MicroRNAs
AUF1; EMT; miR-141/miR-146b-5p; p16INK4a; senescence