Glioma stem-like cells evade interferon suppression through MBD3/NuRD complex–mediated STAT1 downregulation
Open Access
- 17 March 2020
- journal article
- research article
- Published by Rockefeller University Press in The Journal of Experimental Medicine
- Vol. 217 (5)
- https://doi.org/10.1084/jem.20191340
Abstract
Type I interferons (IFNs) are known to mediate antineoplastic effects during tumor progression. Type I IFNs can be produced by multiple cell types in the tumor microenvironment; however, the molecular mechanisms by which tumor cells evade the inhibition of immune microenvironment remain unknown. Here we demonstrate that glioma stem-like cells (GSCs) evade type I IFN suppression through downregulation of STAT1 to initiate tumor growth under inhospitable conditions. The downregulation of STAT1 is mediated by MBD3, an epigenetic regulator. MBD3 is preferentially expressed in GSCs and recruits NuRD complex to STAT1 promoter to suppress STAT1 expression by histone deacetylation. Importantly, STAT1 overexpression or MBD3 depletion induces p21 transcription, resensitizes GSCs to IFN suppression, attenuates GSC tumor growth, and prolongs animal survival. Our findings demonstrate that inactivation of STAT1 signaling by MBD3/NuRD provides GSCs with a survival advantage to escape type I IFN suppression, suggesting that targeting MBD3 may represent a promising therapeutic opportunity to compromise GSC tumorigenic potential.Keywords
Funding Information
- National Key Research and Development Program of China (2017YFA0505602, 2017YFC1601100, 2017YFC1601101, 2017YFC1601102, 2017YFC1601104)
- National Natural Science Foundation of China (81521064, 81872408, 81572889, 31570837, 81790252, 31430021, 81672275)
This publication has 74 references indexed in Scilit:
- Brain tumor initiating cells adapt to restricted nutrition through preferential glucose uptakeNature Neuroscience, 2013
- NuRD and Pluripotency: A Complex Balancing ActCell Stem Cell, 2012
- NuRD Suppresses Pluripotency Gene Expression to Promote Transcriptional Heterogeneity and Lineage CommitmentCell Stem Cell, 2012
- NuRD-mediated deacetylation of H3K27 facilitates recruitment of Polycomb Repressive Complex 2 to direct gene repressionThe EMBO Journal, 2011
- Glioma Stem Cell Proliferation and Tumor Growth Are Promoted by Nitric Oxide Synthase-2Cell, 2011
- Deadly Teamwork: Neural Cancer Stem Cells and the Tumor MicroenvironmentCell Stem Cell, 2011
- p21 in cancer: intricate networks and multiple activitiesNature Reviews Cancer, 2009
- Effects of radiotherapy with concomitant and adjuvant temozolomide versus radiotherapy alone on survival in glioblastoma in a randomised phase III study: 5-year analysis of the EORTC-NCIC trialThe Lancet Oncology, 2009
- PTEN/PI3K/Akt Pathway Regulates the Side Population Phenotype and ABCG2 Activity in Glioma Tumor Stem-like CellsCell Stem Cell, 2009
- Keeping things quiet: Roles of NuRD and Sin3 co-repressor complexes during mammalian developmentThe International Journal of Biochemistry & Cell Biology, 2009