SWI/SNF complex mutations promote thyroid tumor progression and insensitivity to redifferentiation therapies Journal Article
| Authors: | Saqcena, M.; Leandro-Garcia, L. J.; Maag, J. L. V.; Tchekmedyian, V.; Krishnamoorthy, G. P.; Tamarapu, P. P.; Tiedje, V.; Reuter, V.; Knauf, J. A.; de Stanchina, E.; Xu, B.; Liao, X. H.; Refetoff, S.; Ghossein, R.; Chi, P.; Ho, A. L.; Koche, R. P.; Fagin, J. A. |
| Article Title: | SWI/SNF complex mutations promote thyroid tumor progression and insensitivity to redifferentiation therapies |
| Abstract: | Mutations of subunits of the SWI/SNF chromatin remodeling complexes occur commonly in cancers of different lineages, including advanced thyroid cancers. Here we show that thyroid-specific loss of Arid1a, Arid2, or Smarcb1 in mouse BRAFV600E-mutant tumors promotes disease progression and decreased survival, associated with lesion-specific effects on chromatin accessibility and differentiation. As compared with normal thyrocytes, BRAFV600E-mutant mouse papillary thyroid cancers have decreased lineage transcription factor expression and accessibility to their target DNA binding sites, leading to impairment of thyroid-differentiated gene expression and radioiodine incorporation, which is rescued by MAPK inhibition. Loss of individual SWI/SNF subunits in BRAF tumors leads to a repressive chromatin state that cannot be reversed by MAPK pathway blockade, rendering them insensitive to its redifferentiation effects. Our results show that SWI/SNF complexes are central to the maintenance of differentiated function in thyroid cancers, and their loss confers radioiodine refractoriness and resistance to MAPK inhibitor–based redifferentiation therapies. Significance: Reprogramming cancer differentiation confers therapeutic benefit in various disease contexts. Oncogenic BRAF silences genes required for radioiodine responsiveness in thyroid cancer. Mutations in SWI/SNF genes result in loss of chromatin accessibility at thyroid lineage specification genes in BRAF-mutant thyroid tumors, rendering them insensitive to the redifferentiation effects of MAPK blockade. © 2020 American Association for Cancer Research. |
| Journal Title: | Cancer Discovery |
| Volume: | 11 |
| Issue: | 5 |
| ISSN: | 2159-8274 |
| Publisher: | American Association for Cancer Research |
| Date Published: | 2021-05-01 |
| Start Page: | 1158 |
| End Page: | 1175 |
| Language: | English |
| DOI: | 10.1158/2159-8290.Cd-20-0735 |
| PUBMED: | 33318036 |
| PROVIDER: | scopus |
| PMCID: | PMC8102308 |
| DOI/URL: | |
| Notes: | Article -- Export Date: 1 June 2021 -- Source: Scopus |
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