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.
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Accession codes
Abbreviations
- miRNA:
-
microRNA
- ncRNA:
-
noncoding RNA
- T-UCR:
-
transcribed-ultraconserved gene
- PCR:
-
polymerase chain reaction
- RT-qPCR:
-
quantitative reverse transcription PCR
- DMOG:
-
dimethyloxalylglycine
- DMSO:
-
dimethyl sulfoxide
- CA9:
-
carbonic anhydrase IX
- HIF:
-
hypoxia-inducible factor
- CRC:
-
colorectal carcinoma
- Cq:
-
quantification cycle
- OGT:
-
O-linked N-acetylglucosamine (GlcNAc) transferase
- HINCUTs:
-
hypoxia-induced noncoding ultraconserved transcripts
- VHL:
-
Von Hippel–Lindau tumor suppressor
- WT:
-
wild type
- FACS:
-
fluorescence activated cell sorting
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Acknowledgements
Dr. Calin is The Alan M. Gewirtz Leukemia and Lymphoma Society Scholar. He is supported also as a Fellow at The University of Texas, MD Anderson Research Trust, as a University of Texas System Regents Research Scholar and by the CLL Global Research Foundation. Work in Dr. Calin’s laboratory is supported in part by the NIH/NCI (CA135444), a Department of Defense Breast Cancer Idea Award, Developmental Research Awards in Breast Cancer, Ovarian Cancer, Brain Cancer, Prostate Cancer, Multiple Myeloma, Leukemia (P50 CA100632) and Head and Neck (P50 CA097007) SPOREs, a SINF MDACC_DKFZ grant in CLL, the Laura and John Arnold Foundation, the RGK Foundation and the Estate of CG Johnson, Jr. Dr. Ling is an Odyssey Fellow, and his work is supported in part by the Odyssey Program and The Estate of CG Johnson, JR at The University of Texas, MD Anderson Cancer Center. Additional support for the research was provided by the Slovenian Research Agency (ARRS) through the Research program P4-0220 to TK and project 30767 to JF. Dr. Ivan is an American Cancer Society Research Scholar (RSG-09-244-01-TBG). Work in Dr. Ivan’s laboratory is also supported by the NIH/NCI (R01 CA155332-01A1). We thank Mei Koh for assistance with the hypoxia experiments. We thank Ashley R. Heath (Sigma-Aldrich, Woodlands, TX, USA) for the siRNA design. STR DNA fingerprinting was performed by the Cancer Center Support grant-funded Characterized Cell Line core, NCI no. CA16672. We thank Ann Sutton (Department of Scientific Publications, MD Anderson Cancer Center) for her help with the editing of this manuscript.
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Authors Contributions
Study concept and design: Calin, Ivan and Kunej; development of methodology: Calin, Ivan, Kunej and Davuluri; acquisition of data: Ferdin, Wu, Nishida, Nicoloso, Shah, Devlin, Ling, Shimizu, Kumar, Cortez and Schmittgen; analysis and interpretation of data: Ferdin, Nishida, Voorhoeve, Reginato, Negrini, Davuluri, Kunej, Ivan and Calin; statistical analysis: Ferracin, Bi, Yang, Czerniak, Zhang and Davuluri; administrative, technical or material support: Shimizu, Schmittgen and Reginato; drafting of the manuscript: Ferdin, Nishida, Kunej, Ivan and Calin. All authors critically reviewed the manuscript and approved the final version.
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Ferdin, J., Nishida, N., Wu, X. et al. HINCUTs in cancer: hypoxia-induced noncoding ultraconserved transcripts. Cell Death Differ 20, 1675–1687 (2013). https://doi.org/10.1038/cdd.2013.119
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DOI: https://doi.org/10.1038/cdd.2013.119
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