A long non-coding RNA targets microRNA miR-34a to regulate colon cancer stem cell asymmetric division

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Abstract

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.

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Lihua Wang

Department of Biological and Environmental Engineering, Cornell University, Ithaca, United States

Competing interests
The authors declare that no competing interests exist.
Pengcheng Bu

Department of Biomedical Engineering, Duke University, Ithaca, United States

Competing interests
The authors declare that no competing interests exist.
Yiwei Ai

Department of Biomedical Engineering, Cornell University, Ithaca, United States

Competing interests
The authors declare that no competing interests exist.
Tara Srinivasan

Department of Biomedical Engineering, Cornell University, Ithaca, United States

Competing interests
The authors declare that no competing interests exist.
Huanhuan Joyce Chen

Meyer Cancer Center, Weill Corenll Medical College, New York, United States

Competing interests
The authors declare that no competing interests exist.
Kun Xiang

Department of Biomedical Engineering, Cornell University, Ithaca, United States

Competing interests
The authors declare that no competing interests exist.
Steven M Lipkin

Deparments of Medicine, Genetic Medicine and Surgery, Weill Cornell Medical College, New York, United States

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The authors declare that no competing interests exist.
Xiling Shen

Department of Biomedical Engineering, Duke University, Durham, United States

For correspondence
xs37@duke.edu

Competing interests
The authors declare that no competing interests exist.

Ethics

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.

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This article is distributed under the terms of the Creative Commons Attribution License permitting unrestricted use and redistribution provided that the original author and source are credited.