SWI/SNF Complex Mutations Promote Thyroid Tumor Progression and Insensitivity to Redifferentiation Therapies.
Cancer Discov
; 11(5): 1158-1175, 2021 05.
Article
in En
| MEDLINE
| ID: mdl-33318036
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.This article is highlighted in the In This Issue feature, p. 995.
Full text:
1
Collection:
01-internacional
Database:
MEDLINE
Main subject:
Transcription Factors
/
Thyroid Neoplasms
/
Chromosomal Proteins, Non-Histone
Type of study:
Prognostic_studies
Limits:
Animals
Language:
En
Journal:
Cancer Discov
Year:
2021
Type:
Article