Montes Resano, Marta5; Nielsen, Morten M4; Maglieri, Giulia5; Jacobsen, Anders4; Højfeldt, Jonas6; Agrawal-Singh, Shuchi7; Hansen, Klaus7; Helin, Kristian6; van de Werken, Harmen J G4; Pedersen, Jakob S4; Lund, Anders H.5
1 Lund Group, BRIC Research Groups, BRIC, Københavns Universitet2 Helin Group, BRIC Research Groups, BRIC, Københavns Universitet3 Hansen Group, BRIC Research Groups, BRIC, Københavns Universitet4 unknown5 Lund Group, BRIC Research Groups, BRIC, Københavns Universitet6 Helin Group, BRIC Research Groups, BRIC, Københavns Universitet7 Hansen Group, BRIC Research Groups, BRIC, Københavns Universitet
Oncogene-induced senescence (OIS) can occur in response to oncogenic insults and is considered an important tumour suppressor mechanism. Here we identify the lncRNA MIR31HG as upregulated in OIS and find that knockdown of MIR31HG promotes a strong p16(INK4A)-dependent senescence phenotype. Under normal conditions, MIR31HG is found in both nucleus and cytoplasm, but following B-RAF expression MIR31HG is located mainly in the cytoplasm. We show that MIR31HG interacts with both INK4A and MIR31HG genomic regions and with Polycomb group (PcG) proteins, and that MIR31HG is required for PcG-mediated repression of the INK4A locus. We further identify a functional enhancer, located between MIR31HG and INK4A, which becomes activated during OIS and interacts with the MIR31HG promoter. Data from melanoma patients show a negative correlation between MIR31HG and p16(INK4A) expression levels, suggesting a role for this transcript in cancer. Hence, our data provide a new lncRNA-mediated regulatory mechanism for the tumour suppressor p16(INK4A).