Biotech Research and Innovation Centre, University of Copenhagen, Ole Maaloes Vej 5, Copenhagen 2200, Denmark.
Department of Molecular Medicine, Århus University Hospital, Skejby, Århus N 8200, Denmark.
Nat Commun. 2015 Apr 24;6:6967. doi: 10.1038/ncomms7967.
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).
癌基因诱导的衰老（OIS）可能会对致癌物质产生反应，被认为是一种重要的肿瘤抑制机制。在这里，我们发现 lncRNA MIR31HG 在 OIS 中上调，并发现敲低 MIR31HG 可促进强烈的 p16(INK4A)依赖性衰老表型。在正常情况下，MIR31HG 存在于细胞核和细胞质中，但在 B-RAF 表达后，MIR31HG 主要位于细胞质中。我们表明，MIR31HG 与 INK4A 和 MIR31HG 基因组区域相互作用，并与多梳组（PcG）蛋白相互作用，并且 MIR31HG 是 PcG 介导的 INK4A 基因座抑制所必需的。我们进一步鉴定了一个功能增强子，位于 MIR31HG 和 INK4A 之间，在 OIS 期间被激活，并与 MIR31HG 启动子相互作用。来自黑色素瘤患者的数据显示，MIR31HG 和 p16(INK4A)表达水平之间存在负相关，表明该转录本在癌症中起作用。因此，我们的数据为肿瘤抑制因子 p16(INK4A)提供了一种新的 lncRNA 介导的调节机制。
