HINCUTs in cancer: Hypoxia-induced noncoding ultraconserved transcripts

J. Ferdin, N. Nishida, X. Wu, M. S. Nicoloso, M. Y. Shah, C. Devlin, H. Ling, M. Shimizu, K. Kumar, M. A. Cortez, M. Ferracin, Y. Bi, D. Yang, B. Czerniak, W. Zhang, T. D. Schmittgen, M. P. Voorhoeve, M. J. Reginato, M. Negrini, R. V. DavuluriT. Kunej, M. Ivan, G. A. Calin

Research output: Contribution to journalArticle

64 Scopus citations

Abstract

Recent data have linked hypoxia, a classic feature of the tumor microenvironment, to the function of specific microRNAs (miRNAs); however, whether hypoxia affects other types of noncoding transcripts is currently unknown. Starting from a genome-wide expression profiling, we demonstrate for the first time a functional link between oxygen deprivation and the modulation of long noncoding transcripts from ultraconserved regions, termed transcribed-ultraconserved regions (T-UCRs). Interestingly, several hypoxia-upregulated T-UCRs, henceforth named 'hypoxia-induced noncoding ultraconserved transcripts' (HINCUTs), are also overexpressed in clinical samples from colon cancer patients. We show that these T-UCRs are predominantly nuclear and that the hypoxia-inducible factor (HIF) is at least partly responsible for the induction of several members of this group. One specific HINCUT, uc.475 (or HINCUT-1) is part of a retained intron of the host protein-coding gene, O-linked N-acetylglucosamine transferase, which is overexpressed in epithelial cancer types. Consistent with the hypothesis that T-UCRs have important function in tumor formation, HINCUT-1 supports cell proliferation specifically under hypoxic conditions and may be critical for optimal O-GlcNAcylation of proteins when oxygen tension is limiting. Our data gives a first glimpse of a novel functional hypoxic network comprising protein-coding transcripts and noncoding RNAs (ncRNAs) from the T-UCRs category.

Original languageEnglish (US)
Pages (from-to)1675-1687
Number of pages13
JournalCell Death and Differentiation
Volume20
Issue number12
DOIs
StatePublished - Dec 1 2013

Keywords

  • colorectal cancer
  • glioblastoma
  • hypoxia
  • OGT
  • Ultraconserved genes

ASJC Scopus subject areas

  • Cell Biology
  • Molecular Biology

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    Ferdin, J., Nishida, N., Wu, X., Nicoloso, M. S., Shah, M. Y., Devlin, C., Ling, H., Shimizu, M., Kumar, K., Cortez, M. A., Ferracin, M., Bi, Y., Yang, D., Czerniak, B., Zhang, W., Schmittgen, T. D., Voorhoeve, M. P., Reginato, M. J., Negrini, M., ... Calin, G. A. (2013). HINCUTs in cancer: Hypoxia-induced noncoding ultraconserved transcripts. Cell Death and Differentiation, 20(12), 1675-1687. https://doi.org/10.1038/cdd.2013.119