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 SlabyAjay Goel, Jaffer A. Ajani, Milan Radovich, George A. Calin

Research output: Contribution to journalArticle

56 Scopus citations

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.

Original languageEnglish (US)
Pages (from-to)113-124
Number of pages12
JournalEBioMedicine
Volume13
DOIs
StatePublished - Nov 1 2016

Keywords

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

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)

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    Ohtsuka, M., Ling, H., Ivan, C., Pichler, M., Matsushita, D., Goblirsch, M., Stiegelbauer, V., Shigeyasu, K., Zhang, X., Chen, M., Vidhu, F., Bartholomeusz, G. A., Toiyama, Y., Kusunoki, M., Doki, Y., Mori, M., Song, S., Gunther, J. R., Krishnan, S., ... Calin, G. A. (2016). H19 Noncoding RNA, an Independent Prognostic Factor, Regulates Essential Rb-E2F and CDK8-β-Catenin Signaling in Colorectal Cancer. EBioMedicine, 13, 113-124. https://doi.org/10.1016/j.ebiom.2016.10.026