The roles of long non-coding RNAs (lncRNAs) in regulating cancer and stem cells are being increasingly appreciated. Its diverse mechanisms provide the regulatory network with a bigger repertoire to increase complexity. Here we report a novel LncRNA, Lnc34a, that is enriched in colon cancer stem cells (CCSCs) and initiates asymmetric division by directly targeting the microRNA miR-34a to cause its spatial imbalance. Lnc34a recruits Dnmt3a via PHB2 and HDAC1 to methylate and deacetylate the miR-34a promoter simultaneously, hence epigenetically silencing miR-34a expression independent of its upstream regulator, p53. Lnc34a levels affect CCSC self-renewal and colorectal cancer (CRC) growth in xenograft models. Lnc34a is upregulated in late-stage CRCs, contributing to epigenetic miR-34a silencing and CRC proliferation. The fact that lncRNA targets microRNA highlights the regulatory complexity of non-coding RNAs (ncRNAs), which occupy the bulk of the genome.
Animal experimentation: All animal experiments were approved by The Cornell Center for Animal Resources and Education (CARE) and followed the protocol (2009-0071 and 2010-0100).
Human subjects: Frozen CRC specimens of different clinical stages were acquired from Weill Cornell Medical College (WCMC) Colon Cancer Biobank. The studies followed informed consent and approval of the IRB committee at Weill Cornell Medical College.
- Michael R Green, Howard Hughes Medical Institute, University of Massachusetts Medical School, United States
© 2016, Wang et al.
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