The lncRNA MIR31HG regulates p16INK4A expression to modulate senescence

Marta Montes, Morten M. Nielsen, Giulia Maglieri, Anders Jacobsen, Jonas Højfeldt, Shuchi Agrawal-Singh, Klaus Hansen, Kristian Helin, Harmen J. G. van de Werken, Jakob S. Pedersen and Anders H. Lund ()
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Marta Montes: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, Copenhagen 2200, Denmark
Morten M. Nielsen: Århus University Hospital
Giulia Maglieri: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, Copenhagen 2200, Denmark
Anders Jacobsen: Computational Biology Center, Memorial Sloan-Kettering Cancer Center
Jonas Højfeldt: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, Copenhagen 2200, Denmark
Shuchi Agrawal-Singh: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, Copenhagen 2200, Denmark
Klaus Hansen: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, Copenhagen 2200, Denmark
Kristian Helin: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, Copenhagen 2200, Denmark
Harmen J. G. van de Werken: Erasmus MC
Jakob S. Pedersen: Århus University Hospital
Anders H. Lund: Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, Copenhagen 2200, Denmark

Nature Communications, 2015, vol. 6, issue 1, 1-15

Abstract: Abstract 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 p16INK4A-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 p16INK4A expression levels, suggesting a role for this transcript in cancer. Hence, our data provide a new lncRNA-mediated regulatory mechanism for the tumour suppressor p16INK4A.

Date: 2015
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DOI: 10.1038/ncomms7967

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