| First Author | Saqcena M | Year | 2021 |
| Journal | Cancer Discov | Volume | 11 |
| Issue | 5 | Pages | 1158-1175 |
| PubMed ID | 33318036 | Mgi Jnum | J:305677 |
| Mgi Id | MGI:6706830 | Doi | 10.1158/2159-8290.CD-20-0735 |
| Citation | Saqcena M, et al. (2021) SWI/SNF Complex Mutations Promote Thyroid Tumor Progression and Insensitivity to Redifferentiation Therapies. Cancer Discov 11(5):1158-1175 |
| abstractText | 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 BRAF(V600E)-mutant tumors promotes disease progression and decreased survival, associated with lesion-specific effects on chromatin accessibility and differentiation. As compared with normal thyrocytes, BRAF(V600E)-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.This article is highlighted in the In This Issue feature, p. 995. |
