title: H19 Noncoding RNA, an Independent Prognostic Factor, Regulates Essential Rb-E2F and CDK8-β-Catenin Signaling in Colorectal Cancer.
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.
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Masahisa
authors: M
authors: Ohtsuka
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA. Electronic address: hling@mdanderson.org.
authors: Hui
authors: H
authors: Ling
authors: 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.
authors: Cristina
authors: C
authors: Ivan
authors: 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.
authors: Martin
authors: M
authors: Pichler
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Daisuke
authors: D
authors: Matsushita
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Matthew
authors: M
authors: Goblirsch
authors: Research Unit for non-coding RNA and genome editing, Division of Oncology, Medical University of Graz, Austria.
authors: Verena
authors: V
authors: Stiegelbauer
authors: Center for Gastrointestinal Research, Baylor Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA.
authors: Kunitoshi
authors: K
authors: Shigeyasu
authors: Center for RNA Interference and Non-Coding RNAs, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Xinna
authors: X
authors: Zhang
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Meng
authors: M
authors: Chen
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Fnu
authors: F
authors: Vidhu
authors: Department of Experimental Therapeutics, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Geoffrey A
authors: GA
authors: Bartholomeusz
authors: Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Mie, Japan.
authors: Yuji
authors: Y
authors: Toiyama
authors: Department of Gastrointestinal and Pediatric Surgery, Division of Reparative Medicine, Institute of Life Sciences, Mie University Graduate School of Medicine, Mie, Japan.
authors: Masato
authors: M
authors: Kusunoki
authors: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors: Yuichiro
authors: Y
authors: Doki
authors: Department of Gastroenterological Surgery, Graduate School of Medicine, Osaka University, Osaka, Japan.
authors: Masaki
authors: M
authors: Mori
authors: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Shumei
authors: S
authors: Song
authors: Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Jillian R
authors: JR
authors: Gunther
authors: Department of Radiation Oncology, Division of Radiation Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Sunil
authors: S
authors: Krishnan
authors: Central European Institute of Technology, Molecular Oncology II, Masaryk University, Brno, Czech Republic.
authors: Ondrej
authors: O
authors: Slaby
authors: Center for Gastrointestinal Research, Baylor Research Institute and Charles A. Sammons Cancer Center, Baylor University Medical Center, Dallas, TX, USA.
authors: Ajay
authors: A
authors: Goel
authors: Department of Gastrointestinal Medical Oncology, The University of Texas MD Anderson Cancer Center, Houston, TX, USA.
authors: Jaffer A
authors: JA
authors: Ajani
authors: Department of Surgery, Medical and Molecular Genetics, Indiana University School of Medicine, Indianapolis, IN, USA.
authors: Milan
authors: M
authors: Radovich
authors: 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.
authors: George A
authors: GA
authors: Calin
mesh_terms: D000818:Animals; D045744:Cell Line, Tumor; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D056850:Cyclin-Dependent Kinase 8 / Q000235:genetics / Q000378:metabolism*; D030561:Databases, Nucleic Acid; D050684:E2F Transcription Factors / Q000378:metabolism*; D020869:Gene Expression Profiling; D015972:Gene Expression Regulation, Neoplastic; D053263:Gene Regulatory Networks; D006801:Humans; D051379:Mice; D011379:Prognosis; D034622:RNA Interference; D062085:RNA, Long Noncoding / Q000235:genetics*; D016160:Retinoblastoma Protein / Q000378:metabolism*; D015398:Signal Transduction; D016019:Survival Analysis; D059467:Transcriptome; D051176:beta Catenin / Q000378:metabolism*
chemical_list: D050684:E2F Transcription Factors; C094335:H19 long non-coding RNA; D062085:RNA, Long Noncoding; D016160:Retinoblastoma Protein; D051176:beta Catenin; D056850:Cyclin-Dependent Kinase 8
keywords: CDK8; Colorectal cancer; E2F; H19; RB1; β-Catenin