小柯机器人

美国华盛顿大学医学系Andrew C. Hsieh研究组发现转录-翻译冲突是细胞转化和癌症进展的障碍。相关论文于2023年4月20日发表在《癌细胞》杂志上。

他们在尿路上皮中发现了一个肿瘤抑制过程，称为转录-翻译冲突，这是由中央染色质重塑成分ARID1A的下调引起的。Arid1a的缺失会引发促增殖转录本的增加，但同时会抑制真核延伸因子2 (eEF2)，从而导致肿瘤抑制。通过提高翻译延伸速度来解决这一冲突，可以有效和精确地合成一个稳定的mRNAs网络，从而导致不受控制的增殖、克隆生长和膀胱癌进展。

他们在ARID1A低的肿瘤患者中观察到类似的现象，这些肿瘤也通过eEF2表现出增加的翻译延伸活性。这些发现具有重要的临床意义，因为ARID1A缺乏而非ARID1A丰富的肿瘤对蛋白质合成的药物抑制敏感。

据悉，这些发现揭示了由转录-翻译冲突产生的致癌压力，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的串扰在促进癌症中的重要性。

附：英文原文

Title: Transcriptional-translational conflict is a barrier to cellular transformation and cancer progression

Author: Sujata Jana, Sandipan Brahma, Sonali Arora, Cynthia L. Wladyka, Patrick Hoang, Steven Blinka, Rowan Hough, Jessie L. Horn, Yuzhen Liu, Li-Jie Wang, Philippe Depeille, Eric Smith, Robert B. Montgomery, John K. Lee, Michael C. Haffner, Funda Vakar-Lopez, Petros Grivas, Jonathan L. Wright, Hung-Ming Lam, Peter C. Black, Jeroen P. Roose, Alexey G. Ryazanov, Arvind R. Subramaniam, Steven Henikoff, Andrew C. Hsieh

Issue&Volume: 2023-04-20

Abstract: 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.

DOI: 10.1016/j.ccell.2023.03.021

Source: https://www.cell.com/cancer-cell/fulltext/S1535-6108(23)00094-6

Cancer Cell：《癌细胞》，创刊于2002年。隶属于细胞出版社，最新IF：38.585
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