A long non-coding RNA targets microRNA miR-34a to regulate colon cancer stem cell asymmetric division
Lihua Wang,
Pengcheng Bu,
Yiwei Ai,
Tara Srinivasan,
Huanhuan Joyce Chen,
Kun Xiang,
Steven M Lipkin,
Xiling Shen
Affiliations
Lihua Wang
Department of Biological and Environmental Engineering, Cornell University, Ithaca, United States
Pengcheng Bu
School of Electrical and Computer Engineering, Cornell University, Ithaca, United States; Department of Biomedical Engineering, Cornell University, Ithaca, United States; Department of Biomedical Engineering, Duke University, Durham, United States
Yiwei Ai
School of Electrical and Computer Engineering, Cornell University, Ithaca, United States; Department of Biomedical Engineering, Cornell University, Ithaca, United States
Tara Srinivasan
Department of Biomedical Engineering, Cornell University, Ithaca, United States
Huanhuan Joyce Chen
Meyer Cancer Center, Weill Corenll Medical College, New York, United States
Kun Xiang
Department of Biomedical Engineering, Cornell University, Ithaca, United States
Steven M Lipkin
Deparments of Medicine, Genetic Medicine and Surgery, Weill Cornell Medical College, New York, United States
Department of Biological and Environmental Engineering, Cornell University, Ithaca, United States; School of Electrical and Computer Engineering, Cornell University, Ithaca, United States; Department of Biomedical Engineering, Cornell University, Ithaca, United States; Department of Biomedical Engineering, Duke University, Durham, United States
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.
