ARID1A:好的,坏的和丑陋的。

P. Peinado, Á. Andrades, Juan Sanjuan-Hidalgo, Jeffrey R. Haswell, J. Álvarez-Pérez, F. Slack, Pedro Medina Vico
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引用次数: 0

摘要

染色质重塑复合体SWI/SNF是目前在许多肿瘤类型中描述的最易突变的重塑因子。传统上,它与肿瘤抑制作用有关,引导细胞机制走向分化途径和DNA修复过程。ARID1A是所有人类恶性肿瘤中突变最多的SWI/SNF亚基。它也被认为是肺腺癌(LUAD)的顶级突变基因之一和重要的驱动基因。然而,缺乏表型研究证实ARID1A在LUAD中的肿瘤抑制作用。我们观察到在LUAD细胞系中ARID1A缺失会显著损害细胞活力并促进细胞凋亡。乍一看,这些结果与最初定义的肿瘤抑制状态相矛盾,不能用涉及其他SWI/SNF亚基或驱动基因的合成致死事件来解释。此外,当我们下调正常肺细胞系中的ARID1A时,我们没有看到细胞活力的显著降低,这表明ARID1A依赖于肿瘤环境。此外,通过对arid1a敲低后的A549进行rna测序,我们发现了一些与细胞凋亡和基因毒性应激反应相关的上调通路。我们发现ARID1A的缺失会增强细胞中的DNA损伤,并引发严重的内质网应激反应,从而促进细胞凋亡。此外,SWI/SNF复合物的其他亚基的蛋白水平在ARID1A后下降,这可以解释DNA修复过程的减少。总之,我们得出结论,一些LUAD细胞系以肿瘤依赖的方式依赖ARID1A的表达。在这些情况下,ARID1A缺失会引发DNA损伤诱导的细胞凋亡,这可能会开辟新的治疗机会。
本文章由计算机程序翻译,如有差异,请以英文原文为准。
ARID1A: The Good, the Bad and the Ugly.
The chromatin-remodeling complex SWI/SNF is the most mutated remodeler that is currently described in many tumor types. Traditionally, it has been associated with a tumor suppressive role, leading the cellular machinery towards differentiation pathways and DNA repair processes. ARID1A is the most mutated SWI/SNF subunit across all human malignancies. It is also considered as one of the top mutated genes in lung adenocarcinoma (LUAD) and an important driver gene. However, there is a lack of phenotypical studies that confirm the tumor suppressive role of ARID1A in LUAD. We have observed that ARID1A depletion in LUAD cell lines significantly impaired cell viability and promoted apoptosis. At first glance, these results contradicted its initially defined tumor suppressor status and could not be explained by synthetic lethal events involving other SWI/SNF subunits or driver genes. In addition, when we down-regulated ARID1A in a normal lung cell line, we did not see a significant reduction of cell viability, suggesting a tumor context dependency of ARID1A. Moreover, after performing RNA-seq in A549 after ARID1A-knockdown, we observed some up-regulated pathways related with apoptosis and genotoxic stress responses. We found that the depletion of ARID1A enhanced DNA damage in cells and triggered a severe ER stress response that promoted apoptosis. In addition, the protein levels of other subunits of the SWI/SNF complex decreased upon ARID1A, which could explain a decrease of the DNA repair processes. Overall, we conclude that some LUAD cell lines are dependent on ARID1A expression in a tumor-dependent manner. In those contexts, ARID1A loss triggers a DNA damage-induced apoptosis, which could open new therapeutic opportunities.
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