DNMT-dependent suppression of microRNA regulates the induction of GBM tumor-propagating phenotype by Oct4 and Sox2

H. Lopez-Bertoni, B. Lal, A. Li, M. Caplan, H. Guerrero-Cázares, C. G. Eberhart, A. Quiñones-Hinojosa, M. Glas, B. Scheffler, J. Laterra, Y. Li

Research output: Contribution to journalArticle

49 Scopus citations

Abstract

Cancer stem-like cells represent poorly differentiated multipotent tumor-propagating cells that contribute disproportionately to therapeutic resistance and tumor recurrence. Transcriptional mechanisms that control the phenotypic conversion of tumor cells lacking tumor-propagating potential to tumor-propagating stem-like cells remain obscure. Here we show that the reprogramming transcription factors Oct4 and Sox2 induce glioblastoma cells to become stem-like and tumor-propagating via a mechanism involving direct DNA methyl transferase (DNMT) promoter transactivation, resulting in global DNA methylation- and DNMT-dependent downregulation of multiple microRNAs (miRNAs). We show that one such downregulated miRNA, miRNA-148a, inhibits glioblastoma cell stem-like properties and tumor-propagating potential. This study identifies a novel and targetable molecular circuit by which glioma cell stemness and tumor-propagating capacity are regulated.

Original languageEnglish (US)
Pages (from-to)3994-4004
Number of pages11
JournalOncogene
Volume34
Issue number30
DOIs
StatePublished - Jul 23 2015

ASJC Scopus subject areas

  • Molecular Biology
  • Genetics
  • Cancer Research

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    Lopez-Bertoni, H., Lal, B., Li, A., Caplan, M., Guerrero-Cázares, H., Eberhart, C. G., Quiñones-Hinojosa, A., Glas, M., Scheffler, B., Laterra, J., & Li, Y. (2015). DNMT-dependent suppression of microRNA regulates the induction of GBM tumor-propagating phenotype by Oct4 and Sox2. Oncogene, 34(30), 3994-4004. https://doi.org/10.1038/onc.2014.334