SWI/SNF Complex Mutations Promote Thyroid Tumor Progression and Insensitivity to Redifferentiation Therapies.
SWI/SNF Complex Mutations Promote Thyroid Tumor Progression and Insensitivity to Redifferentiation Therapies.
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DOI：
10.1158/2159-8290.cd-20-0735
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发表时间：
2021-05
期刊：
影响因子：
28.2
通讯作者：
Fagin JA
中科院分区：
文献类型：
--
作者：
Saqcena M;Leandro-Garcia LJ;Maag JLV;Tchekmedyian V;Krishnamoorthy GP;Tamarapu PP;Tiedje V;Reuter V;Knauf JA;de Stanchina E;Xu B;Liao XH;Refetoff S;Ghossein R;Chi P;Ho AL;Koche RP;Fagin JA
SWI/SNF染色质重塑复合体亚单位的突变在不同家系的癌症中普遍存在，包括晚期甲状腺癌。在这里，我们表明，在小鼠BRAFV600E突变肿瘤中，甲状腺特异性的ARID1A、ARID2或SMARCB1的缺失促进了疾病的进展和生存率的下降，与病变特异性对染色质可及性和分化的影响有关。与正常甲状腺细胞相比，BRAFV600E突变的小鼠PTCs的谱系转录因子表达和与其靶DNA结合位点的可及性降低，导致甲状腺分化基因表达和放射性碘掺入受损，这可以通过抑制MAPK来挽救。BRAF肿瘤中单个Swi/SNF亚基的缺失导致染色质的抑制状态，而MAPK通路的阻断不能逆转这种状态，使它们对其再分化效应不敏感。我们的结果表明，SWI/SNF复合体是维持甲状腺癌分化功能的中心，它们的缺失使放射性碘不耐受，并对基于MAPK抑制剂的再分化治疗产生抵抗。
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 to normal thyrocytes, BrafV600E-mutant mouse PTCs 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.