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.

Center for Gastrointestinal Research Baylor Research Institute and Charles A Sammons Cancer Center Baylor University Medical Center Dallas TX USA

Center for RNA Interference and Non Coding RNAs The University of Texas MD Anderson Cancer Center Houston TX USA

Central European Institute of Technology Molecular Oncology 2 Masaryk University Brno Czech Republic

Department of Experimental Therapeutics The University of Texas MD Anderson Cancer Center Houston TX USA

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

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

Department of Gastroenterological Surgery Graduate School of Medicine Osaka University Osaka Japan

Department of Gastrointestinal and Pediatric Surgery Division of Reparative Medicine Institute of Life Sciences Mie University Graduate School of Medicine Mie Japan

Department of Gastrointestinal Medical Oncology The University of Texas MD Anderson Cancer Center Houston TX USA

Department of Radiation Oncology Division of Radiation Oncology The University of Texas MD Anderson Cancer Center Houston TX USA

Department of Surgery Medical and Molecular Genetics Indiana University School of Medicine Indianapolis IN USA

Research Unit for non coding RNA and genome editing Division of Oncology Medical University of Graz Austria

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