我们在尿道上皮发现了一种肿瘤抑制过程，称为转录-翻译冲突，由于中央染色质重塑组分ARID1A的失调引起。Arid1a的缺失会引发一系列促增殖转录本的交错，但同时会抑制真核延伸因子2（eEF2），从而实现肿瘤抑制。通过增强转录延伸速度解决这种冲突，可以有效而精确地合成一系列准备好的mRNA网络，导致不受控制的增殖、克隆生长和膀胱癌进展。我们在ARID1A低的肿瘤患者中观察到类似的现象，他们也通过eEF2表现出增加的转录延伸活性。这些发现具有重要的临床意义，因为ARID1A缺失但不是ARID1A正常的肿瘤对蛋白质合成的药物抑制敏感。这些发现揭示了由转录-翻译冲突引起的致癌压力，并提供了一个统一的基因表达模型，揭示了转录和翻译之间交流在促进癌症中的重要性。Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.

We uncover a tumor-suppressive process in urothelium called transcriptional-translational conflict caused by deregulation of the central chromatin remodeling component ARID1A. Loss of Arid1a triggers an increase in a nexus of pro-proliferation transcripts, but a simultaneous inhibition of the eukaryotic elongation factor 2 (eEF2), which results in tumor suppression. Resolution of this conflict through enhancing translation elongation speed enables the efficient and precise synthesis of a network of poised mRNAs resulting in uncontrolled proliferation, clonogenic growth, and bladder cancer progression. We observe a similar phenomenon in patients with ARID1A-low tumors, which also exhibit increased translation elongation activity through eEF2. These findings have important clinical implications because ARID1A-deficient, but not ARID1A-proficient, tumors are sensitive to pharmacologic inhibition of protein synthesis. These discoveries reveal an oncogenic stress created by transcriptional-translational conflict and provide a unified gene expression model that unveils the importance of the crosstalk between transcription and translation in promoting cancer.Copyright © 2023 The Author(s). Published by Elsevier Inc. All rights reserved.