Abstract

DNA methylation is a reversible process catalyzed by the ten–eleven translocation (TET) family of enzymes (TET1, TET2, TET3) that convert 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC). Altered patterns of 5hmC and 5mC are widely reported in human cancers and loss of 5hmC correlates with poor prognosis. Understanding the mechanisms leading to 5hmC loss and its role in oncogenesis will advance the development of epigenetic-based therapeutics. We show that TET2 loss associates with glioblastoma (GBM) stem cells and correlates with poor survival of GBM patients. We further identify a SOX2:miR-10b-5p:TET2 axis that represses TET2 expression, represses 5hmC, increases 5mC levels, and induces GBM cell stemness and tumor-propagating potential. In vivo delivery of a miR-10b-5p inhibitor that normalizes TET2 expression and 5hmC levels inhibits tumor growth and prolongs survival of animals bearing pre-established orthotopic GBM xenografts. These findings highlight the importance of TET2 and 5hmC loss in Sox2-driven oncogenesis and their potential for therapeutic targeting.

Details

Title
Sox2 induces glioblastoma cell stemness and tumor propagation by repressing TET2 and deregulating 5hmC and 5mC DNA modifications
Author
Lopez-Bertoni, Hernando 1   VIAFID ORCID Logo  ; Johnson, Amanda 1   VIAFID ORCID Logo  ; Yuan, Rui 2 ; Lal Bachchu 1 ; Sall, Sophie 3 ; Malloy, Maureen 4 ; Coulter, Jonathan B 5 ; Lugo-Fagundo, Maria 3 ; Shudir Sweta 3 ; Harmon, Khela 3   VIAFID ORCID Logo  ; Caputo, Christopher 3 ; Green, Jordan J 6   VIAFID ORCID Logo  ; Laterra, John 7 

1  Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, USA (GRID:grid.240023.7) (ISNI:0000 0004 0427 667X); Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
2  Johns Hopkins University School of Medicine, Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
3  Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, USA (GRID:grid.240023.7) (ISNI:0000 0004 0427 667X) 
4  The Johns Hopkins University School of Medicine, Bloomberg School of Public Health, Department of Environmental Health and Engineering, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
5  The Johns Hopkins University School of Medicine, Bloomberg School of Public Health, Department of Environmental Health and Engineering, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); The Johns Hopkins University School of Medicine, The Department of Radiation Oncology and Molecular Radiation Sciences, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
6  Johns Hopkins University School of Medicine, Department of Biomedical Engineering, Institute for NanoBioTechnology, and the Translational Tissue Engineering Center, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins University School of Medicine, Department of Ophthalmology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins University School of Medicine, Department of Oncology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins University, Departments of Materials Science & Engineering and Chemical & Biomolecular Engineering, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins University School of Medicine, Department of Neurosurgery, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
7  Hugo W. Moser Research Institute at Kennedy Krieger, Baltimore, USA (GRID:grid.240023.7) (ISNI:0000 0004 0427 667X); Johns Hopkins University School of Medicine, Department of Neurology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins University School of Medicine, Department of Oncology, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311); Johns Hopkins University School of Medicine, Department of Neuroscience, Baltimore, USA (GRID:grid.21107.35) (ISNI:0000 0001 2171 9311) 
Publication year
2022
Publication date
2022
Publisher
Nature Publishing Group
ISSN
20959907
e-ISSN
20593635
Source type
Scholarly Journal
Language of publication
English
DOI
https://doi.org/10.1038/s41392-021-00857-0
ProQuest document ID
2626455676
Copyright
© The Author(s) 2022. This work is published under http://creativecommons.org/licenses/by/4.0/ (the “License”). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.