H19 Noncoding RNA, an Independent Prognostic Factor, Regulates Essential Rb-E2F and CDK8-β-Catenin Signaling in Colorectal Cancer
Masahisa Ohtsuka,
Hui Ling,
Cristina Ivan,
Martin Pichler,
Daisuke Matsushita,
Matthew Goblirsch,
Verena Stiegelbauer,
Kunitoshi Shigeyasu,
Xinna Zhang,
Meng Chen,
Fnu Vidhu,
Geoffrey A. Bartholomeusz,
Yuji Toiyama,
Masato Kusunoki,
Yuichiro Doki,
Masaki Mori,
Shumei Song,
Jillian R. Gunther,
Sunil Krishnan,
Ondrej Slaby,
Ajay Goel,
Jaffer A. Ajani,
Milan Radovich,
George A. Calin
Affiliations
Masahisa Ohtsuka
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Hui Ling
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Cristina Ivan
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Martin Pichler
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Daisuke Matsushita
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Matthew Goblirsch
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Verena Stiegelbauer
Research Unit for non-coding RNA and genome editing, Division of Oncology, Medical University of Graz, Austria
Kunitoshi Shigeyasu
Center for Gastrointestinal Research, Baylor Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
Xinna Zhang
Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Meng Chen
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Fnu Vidhu
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Geoffrey A. Bartholomeusz
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Yuji Toiyama
Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Mie, Japan
Masato Kusunoki
Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Mie, Japan
Yuichiro Doki
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
Masaki Mori
Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan
Shumei Song
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Jillian R. Gunther
Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Sunil Krishnan
Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Ondrej Slaby
Central European Institute of Technology, Molecular Oncology II, Masaryk University, Brno, Czech Republic
Ajay Goel
Center for Gastrointestinal Research, Baylor Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA
Jaffer A. Ajani
Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
Milan Radovich
Department of Surgery, Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA
George A. Calin
Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA
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.
