HINCUTs in cancer: hypoxia-induced noncoding ultraconserved transcripts.

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.

• Authors: 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 Davuluri, T Kunej, M Ivan, G A Calin
• Journal: Cell death and differentiation (Cell Death Differ) Vol. 20 Issue 12 Pg. 1675-87 (Dec 2013) ISSN: 1476-5403 [Electronic] England
• PMID: 24037088 (Publication Type: Journal Article, Research Support, N.I.H., Extramural, Research Support, Non-U.S. Gov't, Research Support, U.S. Gov't, Non-P.H.S.)

Chemical References

• DNA, Neoplasm
• Hypoxia-Inducible Factor 1, alpha Subunit
• RNA, Messenger
• RNA, Untranslated
• N-Acetylglucosaminyltransferases
• UDP-N-acetylglucosamine-peptide beta-N-acetylglucosaminyltransferase

Topics

• Cell Hypoxia (genetics)
• Cell Line, Tumor
• Conserved Sequence (genetics)
• DNA, Neoplasm (genetics)
• Down-Regulation (genetics)
• Enhancer Elements, Genetic (genetics)
• Gene Expression Regulation, Neoplastic
• Genetic Loci (genetics)
• Humans
• Hypoxia-Inducible Factor 1, alpha Subunit (metabolism)
• N-Acetylglucosaminyltransferases (genetics, metabolism)
• Neoplasms (enzymology, genetics, pathology)
• RNA, Messenger (genetics, metabolism)
• RNA, Untranslated (genetics)
• Reproducibility of Results
• Transcription, Genetic