Gene body methylation of the lymphocyte-specific gene card11 results in its overexpression and regulates cancer mTOR signaling

Michael H. McGuire, Santosh K. Dasari, Hui Yao, Yunfei Wen, Lingegowda S. Mangala, Emine Bayraktar, Wencai Ma, Cristina Ivan, Einav Shoshan, Sherry Y. Wu, Eric Jonasch, Menashe Bar-Eli, Jing Wang, Keith A. Baggerly, Anil K. Sood

Research output: Contribution to journalArticlepeer-review

3 Scopus citations

Abstract

Investigations into the function of nonpromoter DNA methylation have yielded new insights into epigenetic regulation of gene expression. Previous studies have highlighted the importance of distinguishing between DNA methylation in discrete functional regions; however, integrated nonpromoter DNA methylation and gene expression analyses across a wide number of tumor types and corresponding normal tissues have not been performed. Through integrated analysis of gene expression and DNA methylation profiles, we examined 32 tumor types and identified 57 tumor suppressors and oncogenes out of 260 genes exhibiting a correlation of > 0.5 between gene body methylation and gene expression in at least one tumor type. The lymphocyte-specific gene CARD11 exhibits robust association between gene body methylation and expression across 19 of 32 tumor types examined. It is significantly overexpressed in kidney renal cell carcinoma (KIRC) and lung adenocarcinoma (LUAD) tumor tissues in comparison with respective control samples; and is significantly associated with lower overall survival in KIRC. Contrary to its canonical function in lymphocyte NFkB activation, CARD11 activates the mTOR pathway in KIRC and LUAD, resulting in suppressed autophagy. Furthermore, demethylation of a CpG island within the gene body of CARD11 decreases gene expression. Collectively, our study highlights how DNA methylation outside the promoter region can impact tumor progression. Implications: Our study describes a novel regulatory role of gene body DNA methylation–dependent CARD11 expression on mTOR signaling and its impact on tumor progression.

Original languageEnglish (US)
Pages (from-to)1917-1928
Number of pages12
JournalMolecular Cancer Research
Volume19
Issue number11
DOIs
StatePublished - Nov 2021

ASJC Scopus subject areas

  • Molecular Biology
  • Oncology
  • Cancer Research

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  • Advanced Technology Genomics Core
  • Cytogenetics and Cell Authentication Core
  • Research Animal Support Facility

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