MYC transcription activation mediated by OCT4 as a mechanism of resistance to 13-cisRA-mediated differentiation in neuroblastoma
Open Access
- 14 May 2020
- journal article
- research article
- Published by Springer Science and Business Media LLC in Cell Death & Disease
- Vol. 11 (5), 1-20
- https://doi.org/10.1038/s41419-020-2563-4
Abstract
Despite the improvement in clinical outcome with 13-cis-retinoic acid (13-cisRA) + anti-GD2 antibody + cytokine immunotherapy given in first response ~40% of high-risk neuroblastoma patients die of recurrent disease. MYCN genomic amplification is a biomarker of aggressive tumors in the childhood cancer neuroblastoma. MYCN expression is downregulated by 13-cisRA, a differentiating agent that is a component of neuroblastoma therapy. Although MYC amplification is rare in neuroblastoma at diagnosis, we report transcriptional activation of MYC medicated by the transcription factor OCT4, functionally replacing MYCN in 13-cisRA-resistant progressive disease neuroblastoma in large panels of patient-derived cell lines and xenograft models. We identified novel OCT4-binding sites in the MYC promoter/enhancer region that regulated MYC expression via phosphorylation by MAPKAPK2 (MK2). OCT4 phosphorylation at the S111 residue by MK2 was upstream of MYC transcriptional activation. Expression of OCT4, MK2, and c-MYC was higher in progressive disease relative to pre-therapy neuroblastomas and was associated with inferior patient survival. OCT4 or MK2 knockdown decreased c-MYC expression and restored the sensitivity to 13-cisRA. In conclusion, we demonstrated that high c-MYC expression independent of genomic amplification is associated with disease progression in neuroblastoma. MK2-mediated OCT4 transcriptional activation is a novel mechanism for activating the MYC oncogene in progressive disease neuroblastoma that provides a therapeutic target.Keywords
Funding Information
- U.S. Department of Health & Human Services | NIH | National Cancer Institute (R01 CA168699, R01 CA221957)
- U.S. Department of Health & Human Services | NIH | National Cancer Institute
- Cancer Prevention and Research Institute of Texas (RP170470, RP130547)
- Alex's Lemonade Stand Foundation for Childhood Cancer
This publication has 64 references indexed in Scilit:
- Phosphorylation regulates human OCT4Proceedings of the National Academy of Sciences of the United States of America, 2012
- PI3K-targeted therapy can be evaded by gene amplification along the MYC-eukaryotic translation initiation factor 4E (eIF4E) axisProceedings of the National Academy of Sciences of the United States of America, 2011
- Oncogenic PIK3CA-driven mammary tumors frequently recur via PI3K pathway–dependent and PI3K pathway–independent mechanismsNature Medicine, 2011
- Anti-GD2 Antibody with GM-CSF, Interleukin-2, and Isotretinoin for NeuroblastomaThe New England Journal of Medicine, 2010
- Post-Translational Regulation of Oct4 Transcriptional ActivityPLOS ONE, 2009
- Specific Knockdown of OCT4 in Human Embryonic Stem Cells by Inducible Short Hairpin RNA InterferenceThe International Journal of Cell Cloning, 2009
- An embryonic stem cell–like gene expression signature in poorly differentiated aggressive human tumorsNature Genetics, 2008
- Induction of Pluripotent Stem Cells from Adult Human Fibroblasts by Defined FactorsCell, 2007
- Induction of Pluripotent Stem Cells from Mouse Embryonic and Adult Fibroblast Cultures by Defined FactorsCell, 2006
- Protocol for the fast chromatin immunoprecipitation (ChIP) methodNature Protocols, 2006