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

2014; Springer Nature; Volume: 34; Issue: 30 Linguagem: Inglês

10.1038/onc.2014.334

1476-5594

Hernando López-Bertoni, Bachchu Lal, Angela Li, Michael J. Caplan, Hugo Guerrero-Cázares, Charles G. Eberhart, Alfredo Quiñones-Hinojosa, Martin Glas, Björn Scheffler, John Laterra, Y Li,

Cancer Cells and Metastasis

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.