The role of non-coding RNAs in senescence
Recent evidence has unveiled the existence of lncRNAs, which are transcribed from non-protein genomic coding regions. Although their precise role has not been fully elucidated, they seem to have important roles in processes such as proliferation or differentiation, and in diseases including cancer. The scope of the EU-funded NONCOSENSE (Identifying long non-coding RNAs with a role in oncogenic-induced senescence) project was to address the implication of lncRNAs in senescence, the process in which cells enter irreversible growth arrest following oncogenic insults or telomere erosion. Researchers designed a custom array platform for lncRNAs to test cells with activated BRAF oncogene such as in the case of mutant melanoma cells. In senescent cells, they detected an upregulation of the lncRNA MIR31HG, which is located approximately 400 Kilobases away from the INK4A locus, a key regulator of cellular senescence. Following siRNA depletion, researchers observed that the cells reduced their growth rate and acquired various senescence features including an increased expression of the cell cycle inhibitor p16INK4A protein. Insight into the mechanism of senescence regulation indicated that MIR31HG interacted with the INK4A promoter and several polycomb group protein repressors of the INK4A locus. Furthermore, depletion of MIR31HG in cells undergoing oncogene-induced senescence affected the secretion of cytokines and interleukins. Interestingly, the factors that reinforced senescence were retained following MIR31HG depletion but the ones responsible for invasion were significantly reduced. Taken together, the activities of the NONCOSENSE study demonstrate for the first time, the bad and good components of the secretome of senescent cells. Importantly, results underscore the therapeutic value of MIR31HG lncRNA in senescent cells.
Keywords
Senescence, cancer, long non-coding RNA, BRAF, melanoma, MIR31HG, INK4A, secretome