PRC2-mediated repression of SMARCA2 predicts EZH2 inhibitor activity in SWI/SNF mutant tumors
PRC2-mediated repression of SMARCA2 predicts EZH2 inhibitor activity in SWI/SNF mutant tumors
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DOI：
10.1073/pnas.1703966114
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发表时间：
2017-11-14
影响因子：
11.1
通讯作者：
Yauch, Robert L.
中科院分区：
文献类型：
--
作者：
Januario, Thomas;Ye, Xiaofen;Yauch, Robert L.
在人类癌症中，SWI/SNF染色质重塑复合体的亚单位经常发生突变，导致表观遗传依赖，这是治疗上的靶向。对多梳抑制复合体(PRC2)和EZH2的依赖代表了SWI/SNF复合体亚单位SNF5突变的肿瘤中的一个这样的脆弱性；然而，这种脆弱性是否延伸到其他SWI/SNF亚单位突变尚不清楚。在这里，我们表明SWI/SNF ATPase突变的癌症子集SMARCA4对EZH2抑制敏感。在不同的模型中，抑制EZH2会导致以衰老和/或细胞凋亡为特征的异质性表型反应，也会导致体内肿瘤的生长抑制。在SMARCA4突变癌症模型中，SMARCA2 Paralog的低表达与细胞对EZH2抑制的敏感性有关，与组织来源无关。在敏感模型中，SMARCA2被PRC2抑制，诱导的SMARCA2表达可以补偿SMARCA4，拮抗PRC2靶点。SMARCA2对EZH2抑制反应的诱导是细胞凋亡所必需的，但不是生长停滞所必需的，这是通过一种涉及组织蛋白酶B去抑制的机制。SMARCA2的表达也描述了EZH2抑制剂对其他SWI/SNF复合亚单位突变肿瘤的敏感性，包括SNF5和ARID1A突变肿瘤。我们的数据支持监测SMARCA2的表达，作为SWI/SNF突变癌症背景下EZH2靶向治疗的预测生物标记物。
Subunits of the SWI/SNF chromatin remodeling complex are frequently mutated in human cancers leading to epigenetic dependencies that are therapeutically targetable. The dependency on the polycomb repressive complex (PRC2) and EZH2 represents one such vulnerability in tumors with mutations in the SWI/SNF complex subunit, SNF5; however, whether this vulnerability extends to other SWI/SNF subunit mutations is not well understood. Here we show that a subset of cancers harboring mutations in the SWI/SNF ATPase, SMARCA4, is sensitive to EZH2 inhibition. EZH2 inhibition results in a heterogenous phenotypic response characterized by senescence and/or apoptosis in different models, and also leads to tumor growth inhibition in vivo. Lower expression of the SMARCA2 paralog was associated with cellular sensitivity to EZH2 inhibition in SMARCA4 mutant cancer models, independent of tissue derivation. SMARCA2 is suppressed by PRC2 in sensitive models, and induced SMARCA2 expression can compensate for SMARCA4 and antagonize PRC2 targets. The induction of SMARCA2 in response to EZH2 inhibition is required for apoptosis, but not for growth arrest, through a mechanism involving the derepression of the lysomal protease cathepsin B. Expression of SMARCA2 also delineates EZH2 inhibitor sensitivity for other SWI/SNF complex subunit mutant tumors, including SNF5 and ARID1Amutant cancers. Our data support monitoring SMARCA2 expression as a predictive biomarker for EZH2 targeted therapies in the context of SWI/SNF mutant cancers.