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Nat Commun. 2018 Jan 8;9(1):100. doi: 10.1038/s41467-017-02601-1.

HoxC5 and miR-615-3p target newly evolved genomic regions to repress hTERT and inhibit tumorigenesis.

Author information

1
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.
2
Cancer Therapeutics and Stratified Oncology, Genome Institute of Singapore, 60 Biopolis Street, Singapore, 138672, Singapore.
3
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, Singapore, 117597, Singapore.
4
Neuroscience Academic Clinical Programme, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.
5
Department of Research, National Neuroscience Institute, 11 Jalan Tan Tock Seng, Singapore, 308433, Singapore.
6
Institute of Medical Biology (IMB), 8A Biomedical Grove, Singapore, 138648, Singapore.
7
Cancer Science Institute of Singapore, National University of Singapore, 14 Medical Drive, Singapore, 117599, Singapore.
8
School of Biological Sciences, Nanyang Technological University, 60 Nanyang Drive, Singapore, 637551, Singapore.
9
Duke-NUS Centre for Computational Biology, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.
10
Cardiovascular and Metabolic Disorders Program, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore.
11
Institute of Molecular and Cell Biology (IMCB), Singapore, 138673, Singapore.
12
Medical Research Council (MRC) Molecular Haematology Unit, Weatherall Institute of Molecular Medicine, Oxford University, Oxford, OX3 9DS, UK.
13
Bioprocessing Technology Institute, 20 Biopolis Street, Singapore, 138669, Singapore.
14
Cellular and Molecular Research, National Cancer Centre, 11 Hospital Drive, Singapore, 169610, Singapore.
15
Cancer and Stem Cell Biology Program, Duke-NUS Medical School, 8 College Road, Singapore, 169857, Singapore. shang.li@duke-nus.edu.sg.
16
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, 2 Medical Drive, Singapore, 117597, Singapore. shang.li@duke-nus.edu.sg.

Abstract

The repression of telomerase activity during cellular differentiation promotes replicative aging and functions as a physiological barrier for tumorigenesis in long-lived mammals, including humans. However, the underlying mechanisms remain largely unclear. Here we describe how miR-615-3p represses hTERT expression. mir-615-3p is located in an intron of the HOXC5 gene, a member of the highly conserved homeobox family of transcription factors controlling embryogenesis and development. Unexpectedly, we found that HoxC5 also represses hTERT expression by disrupting the long-range interaction between hTERT promoter and its distal enhancer. The 3'UTR of hTERT and its upstream enhancer region are well conserved in long-lived primates. Both mir-615-3p and HOXC5 are activated upon differentiation, which constitute a feed-forward loop that coordinates transcriptional and post-transcriptional repression of hTERT during cellular differentiation. Deregulation of HOXC5 and mir-615-3p expression may contribute to the activation of hTERT in human cancers.

PMID:
29311615
PMCID:
PMC5758779
DOI:
10.1038/s41467-017-02601-1
[Indexed for MEDLINE]
Free PMC Article

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