Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins
Sensitivity of human lung adenocarcinoma cell lines to targeted inhibition of BET epigenetic signaling proteins
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DOI：
10.1073/pnas.1216363109
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发表时间：
2012-11-20
影响因子：
11.1
通讯作者：
Varmus, Harold
中科院分区：
文献类型：
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作者：
Lockwood, William W.;Zejnullahu, Kreshnik;Varmus, Harold
溴结构域和额外末端结构域（BET）蛋白作为表观遗传信号传导因子起作用，其与乙酰化组蛋白缔合并促进靶基因的转录。靶向BET蛋白活性的抑制剂通过抑制c-MYC和下游靶基因在血液癌症中显示出有效的抗增殖作用。然而，由于细胞的表观遗传景观取决于谱系而急剧变化，预期转录共激活因子如BET在源自不同来源细胞的癌症中具有不同的靶标，这可能影响BET抑制剂的活性和作用机制。为了验证这一假设，我们用BET抑制剂JQ 1处理了一组肺腺癌（LAC）细胞系，发现一个亚组对BET抑制非常敏感。与血液肿瘤相比，我们发现LAC细胞通过一种独立于cMYC下调的机制被JQ 1抑制。通过基因表达谱分析，我们发现致癌转录因子FOSL 1及其靶点被JQ 1以剂量依赖性方式抑制。BRD 4的敲除也降低了FOSL 1水平，并且FOSL 1的抑制表现为JQ 1处理的效果，这表明该转录因子的丢失可能部分地导致LAC细胞中BET抑制的细胞毒性作用，尽管FOSL 1单独的异位表达并不能挽救表型。总之，这些发现表明BET抑制剂可能在实体瘤中是有用的，并且BET的转录靶点的细胞谱系特异性差异可能影响这些蛋白质的抑制剂在不同癌症类型中的活性。
Bromodomain and extra terminal domain (BET) proteins function as epigenetic signaling factors that associate with acetylated histones and facilitate transcription of target genes. Inhibitors targeting the activity of BET proteins have shown potent antiproliferative effects in hematological cancers through the suppression of c-MYC and downstream target genes. However, as the epigenetic landscape of a cell varies drastically depending on lineage, transcriptional coactivators such as BETs would be expected to have different targets in cancers derived from different cells of origin, and this may influence the activity and mechanism of action of BET inhibitors. To test this hypothesis, we treated a panel of lung adenocarcinoma (LAC) cell lines with the BET inhibitor JQ1 and found that a subset is acutely susceptible to BET inhibition. In contrast to blood tumors, we showthat LAC cells are inhibited by JQ1 through a mechanism independent of cMYC down-regulation. Through gene expression profiling, we discovered that the oncogenic transcription factor FOSL1 and its targets are suppressed by JQ1 in a dose-dependant manner. Knockdown of BRD4 also decreased FOSL1 levels, and inhibition of FOSL1 phenocopied the effects of JQ1 treatment, suggesting that loss of this transcription factor may be partly responsible for the cytotoxic effects of BET inhibition in LAC cells, although ectopic expression of FOSL1 alone did not rescue the phenotype. Together, these findings suggest that BET inhibitors may be useful in solid tumors and that cell-lineage-specific differences in transcriptional targets of BETs may influence the activity of inhibitors of these proteins in different cancer types.