Epigenetic modulation of a miR-296-5p: HMGA1 axis regulates Sox2 expression and glioblastoma stem cells

H. Lopez-Bertoni, B. Lal, N. Michelson, H. Guerrero-Cázares, A. Quiñones-Hinojosa, Y. Li, J. Laterra

Research output: Contribution to journalArticle

Abstract

Solid malignancies contain subsets of multipotent cells that grow as spheres and efficiently propagate tumors in xenograft models, reflecting a stem-like, self-renewing and tumor-propagating phenotype. These cancer ‘stem cells (SCs)’ have been shown to maintain tumor growth, contribute to resistance and drive tumor recurrence. Cancer cell stemness is dynamically influenced by epigenetic mechanisms and differentially regulated coding and noncoding RNAs. How these mechanisms specifically contribute to the generation and/or maintenance of cancer SCs remains unclear. This study identifies a novel epigenetically regulated circuit that integrates microRNA, chromatin remodeling and the reprogramming transcription factor Sox2 to regulate glioblastoma (GBM)-propagating SCs. We show that miR-296-5p expression is repressed in a DNA methylation-dependent manner under conditions that promote GBM cell stemness and that miR-296-5p inhibits GBM cell stemness and their capacity to self-renew as spheres and propagate glioma xenografts in vivo. We show that the chromatin remodeling protein HMGA1 functions as a downstream effector of these biological responses to miR-296-5p and regulates Sox2 expression, a master driver of cell stemness, by modifying chromatin architecture at the Sox2 promoter. These results show for the first time that miR-296-5p inhibits transcriptional mechanisms that support GBM SCs and identify a miR-296-5p:HMGA1:Sox2 axis as a novel regulator of GBM SCs and candidate pathway for targeting therapies directed at depleting tumors of their tumor-propagating stem cell subsets.Oncogene advance online publication, 22 February 2016; doi:10.1038/onc.2016.22.

Original languageEnglish (US)
JournalOncogene
DOIs
StateAccepted/In press - Feb 22 2016

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Glioblastoma
Epigenomics
Stem Cells
Neoplasms
Neoplastic Stem Cells
Chromatin Assembly and Disassembly
Heterografts
Untranslated RNA
DNA Methylation
MicroRNAs
Oncogenes
Glioma
Chromatin
Transcription Factors
Phenotype
Recurrence
Proteins

ASJC Scopus subject areas

  • Molecular Biology
  • Cancer Research
  • Genetics

Cite this

Lopez-Bertoni, H., Lal, B., Michelson, N., Guerrero-Cázares, H., Quiñones-Hinojosa, A., Li, Y., & Laterra, J. (2016). Epigenetic modulation of a miR-296-5p: HMGA1 axis regulates Sox2 expression and glioblastoma stem cells. Oncogene. DOI: 10.1038/onc.2016.22

Epigenetic modulation of a miR-296-5p : HMGA1 axis regulates Sox2 expression and glioblastoma stem cells. / Lopez-Bertoni, H.; Lal, B.; Michelson, N.; Guerrero-Cázares, H.; Quiñones-Hinojosa, A.; Li, Y.; Laterra, J.

In: Oncogene, 22.02.2016.

Research output: Contribution to journalArticle

Lopez-Bertoni H, Lal B, Michelson N, Guerrero-Cázares H, Quiñones-Hinojosa A, Li Y et al. Epigenetic modulation of a miR-296-5p: HMGA1 axis regulates Sox2 expression and glioblastoma stem cells. Oncogene. 2016 Feb 22. Available from, DOI: 10.1038/onc.2016.22

Lopez-Bertoni, H.; Lal, B.; Michelson, N.; Guerrero-Cázares, H.; Quiñones-Hinojosa, A.; Li, Y.; Laterra, J. / Epigenetic modulation of a miR-296-5p : HMGA1 axis regulates Sox2 expression and glioblastoma stem cells.

In: Oncogene, 22.02.2016.

Research output: Contribution to journalArticle

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