Journal
CELL DEATH AND DIFFERENTIATION
Volume 20, Issue 12, Pages 1675-1687Publisher
NATURE PUBLISHING GROUP
DOI: 10.1038/cdd.2013.119
Keywords
ultraconserved genes; colorectal cancer; glioblastoma; hypoxia; OGT
Categories
Funding
- Fellow at The University of Texas
- MD Anderson Research Trust
- CLL Global Research Foundation
- NIH/NCI [CA135444, R01 CA155332-01A1]
- Department of Defense Breast Cancer Idea Award
- Developmental Research Award [P50 CA097007, P50 CA100632]
- SINF MDACC_DKFZ grant in CLL
- Laura and John Arnold Foundation
- RGK Foundation
- Estate of CG Johnson
- Slovenian Research Agency (ARRS) [P4-0220, 30767]
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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.
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