PDF(Pubmed)
Abstract：
SMARCB1, a subunit of the SWI/SNF chromatin remodeling complex, is the causative gene of rhabdoid tumors and epithelioid sarcomas. Here, we identify a paralog pair of CBP and p300 as a synthetic lethal target in SMARCB1-deficient cancers by using a dual siRNA screening method based on the \"simultaneous inhibition of a paralog pair\" concept. Treatment with CBP/p300 dual inhibitors suppresses growth of cell lines and tumor xenografts derived from SMARCB1-deficient cells but not from SMARCB1-proficient cells. SMARCB1-containing SWI/SNF complexes localize with H3K27me3 and its methyltransferase EZH2 at the promotor region of the KREMEN2 locus, resulting in transcriptional downregulation of KREMEN2. By contrast, SMARCB1 deficiency leads to localization of H3K27ac, and recruitment of its acetyltransferases CBP and p300, at the KREMEN2 locus, resulting in transcriptional upregulation of KREMEN2, which cooperates with the SMARCA1 chromatin remodeling complex. Simultaneous inhibition of CBP/p300 leads to transcriptional downregulation of KREMEN2, followed by apoptosis induction via monomerization of KREMEN1 due to a failure to interact with KREMEN2, which suppresses anti-apoptotic signaling pathways. Taken together, our findings indicate that simultaneous inhibitors of CBP/p300 could be promising therapeutic agents for SMARCB1-deficient cancers.
摘要：
SMARCB1，SWI/SNF染色质重塑复合物的一个亚基，是横纹肌样肿瘤和上皮样肉瘤的致病基因。这里,我们使用基于"同时抑制同系物对"概念的双重siRNA筛选方法,鉴定了CBP和p300的同系物对作为SMARCB1缺陷型癌症的合成致死靶标.用CBP/p300双重抑制剂处理抑制源自SMARCB1缺陷细胞但不源自SMARCB1丰富细胞的细胞系和肿瘤异种移植物的生长。含有SMARCB1的SWI/SNF复合物与H3K27me3及其甲基转移酶EZH2定位于KREMEN2基因座的启动子区，导致KREMEN2的转录下调。相比之下,SMARCB1缺乏导致H3K27ac的定位，并在KREMEN2基因座处募集其乙酰转移酶CBP和p300，导致与SMARCA1染色质重塑复合物协同作用的KREMEN2转录上调。CBP/p300的同时抑制导致KREMEN2的转录下调，随后由于与KREMEN2相互作用失败而通过KREMEN1的单核细胞化诱导凋亡，从而抑制抗凋亡信号通路。一起来看,我们的研究结果表明,CBP/p300的同时抑制剂可能是SMARCB1缺陷型癌症的有前景的治疗药物.
