TY - JOUR
T1 - DNMT-dependent suppression of microRNA regulates the induction of GBM tumor-propagating phenotype by Oct4 and Sox2
AU - Lopez-Bertoni, H.
AU - Lal, B.
AU - Li, A.
AU - Caplan, M.
AU - Guerrero-Cázares, H.
AU - Eberhart, C. G.
AU - Quiñones-Hinojosa, A.
AU - Glas, M.
AU - Scheffler, B.
AU - Laterra, J.
AU - Li, Y.
N1 - Funding Information:
We thank Daniel Trageser for technical assistance. This work was financially supported by grants from the American Brain Tumor Association (YL), James S McDonnell Foundation (JL), and the United States NIH grants RO1NS073611 (JL) and R01NS070024 (AQ-H).
Publisher Copyright:
© 2015 Macmillan Publishers Limited All rights reserved.
PY - 2015/7/23
Y1 - 2015/7/23
N2 - 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.
AB - 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.
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U2 - 10.1038/onc.2014.334
DO - 10.1038/onc.2014.334
M3 - Article
C2 - 25328136
AN - SCOPUS:84937887675
SN - 0950-9232
VL - 34
SP - 3994
EP - 4004
JO - Oncogene
JF - Oncogene
IS - 30
ER -