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EBioMedicine. 2016 Nov;13:113-124. doi: 10.1016/j.ebiom.2016.10.026. Epub 2016 Oct 19.

H19 Noncoding RNA, an Independent Prognostic Factor, Regulates Essential Rb-E2F and CDK8-β-Catenin Signaling in Colorectal Cancer.

Author information

1
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
2
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: hling@mdanderson.org.
3
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
4
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Research Unit for non-coding RNA and genome editing, Division of Oncology, Medical University of Graz, Austria.
5
Research Unit for non-coding RNA and genome editing, Division of Oncology, Medical University of Graz, Austria.
6
Center for Gastrointestinal Research, Baylor Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA.
7
Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
8
Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Mie, Japan.
9
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
10
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
11
Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
12
Central European Institute of Technology, Molecular Oncology II, Masaryk University, Brno, Czech Republic.
13
Department of Surgery, Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
14
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA; Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: gcalin@mdanderson.org.

Abstract

The clinical significance of long noncoding RNAs (lncRNAs) in colorectal cancer (CRC) remains largely unexplored. Here, we analyzed a large panel of lncRNA candidates with The Cancer Genome Atlas (TCGA) CRC dataset, and identified H19 as the most significant lncRNA associated with CRC patient survival. We further validated such association in two independent CRC cohorts. H19 silencing blocked G1-S transition, reduced cell proliferation, and inhibited cell migration. We profiled gene expression changes to gain mechanism insight of H19 function. Transcriptome data analysis revealed not only previously identified mechanisms such as Let-7 regulation by H19, but also RB1-E2F1 function and β-catenin activity as essential upstream regulators mediating H19 function. Our experimental data showed that H19 affects phosphorylation of RB1 protein by regulating gene expression of CDK4 and CCND1. We further demonstrated that reduced CDK8 expression underlies changes of β-catenin activity, and identified that H19 interacts with macroH2A, an essential regulator of CDK8 gene transcription. However, the relevance of H19-macroH2A interaction in CDK8 regulation remains to be experimentally determined. We further explored the clinical relevance of above mechanisms in clinical samples, and showed that combined analysis of H19 with its targets improved prognostic value of H19 in CRC.

KEYWORDS:

CDK8; Colorectal cancer; E2F; H19; RB1; β-Catenin

PMID:
27789274
PMCID:
PMC5264449
DOI:
10.1016/j.ebiom.2016.10.026
[Indexed for MEDLINE]
Free PMC Article

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