ARID1A loss in neuroblastoma promotes the adrenergic-to-mesenchymal transition by regulating enhancer-mediated gene expression
- Shi, H., Tao, T., Abraham, B.J., Durbin, A.D., Zimmerman, M.W., Kadoch, C., Look, A.T.
- Science advances 6: eaaz3440 (Journal)
- Registered Authors
- Look, A. Thomas, Zimmerman, Mark
- MeSH Terms
- 32832616 Full text @ Sci Adv
Shi, H., Tao, T., Abraham, B.J., Durbin, A.D., Zimmerman, M.W., Kadoch, C., Look, A.T. (2020) ARID1A loss in neuroblastoma promotes the adrenergic-to-mesenchymal transition by regulating enhancer-mediated gene expression. Science advances. 6:eaaz3440.
Mutations in genes encoding SWI/SNF chromatin remodeling complexes are found in approximately 20% of all human cancers, with ARID1A being the most frequently mutated subunit. Here, we show that disruption of ARID1A homologs in a zebrafish model accelerates the onset and increases the penetrance of MYCN-driven neuroblastoma by increasing cell proliferation in the sympathoadrenal lineage. Depletion of ARID1A in human NGP neuroblastoma cells promoted the adrenergic-to-mesenchymal transition with changes in enhancer-mediated gene expression due to alterations in the genomic occupancies of distinct SWI/SNF assemblies, BAF and PBAF. Our findings indicate that ARID1A is a haploinsufficient tumor suppressor in MYCN-driven neuroblastoma, whose depletion enhances tumor development and promotes the emergence of the more drug-resistant mesenchymal cell state.
Genes / Markers
Mutation and Transgenics
Human Disease / Model Data
Sequence Targeting Reagents
Engineered Foreign Genes
Errata and Notes