Deubiquitinase OTUD6B Isoforms Are Important Regulators of Growth and Proliferation.
Deubiquitinase OTUD6B Isoforms Are Important Regulators of Growth and Proliferation.
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DOI：
10.1158/1541-7786.mcr-16-0281-t
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发表时间：
2017-02
期刊：
影响因子：
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通讯作者：
Bocchetta M
中科院分区：
文献类型：
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作者：
Sobol A;Askonas C;Alani S;Weber MJ;Ananthanarayanan V;Osipo C;Bocchetta M
去泛素化酶（DUB）越来越多地与正常细胞和癌细胞中的基本过程的调节相关，包括DNA复制和修复、程序性细胞死亡以及癌基因和肿瘤抑制因子信号传导。在这里，有证据表明，去泛素化酶OTUD 6 B调节非小细胞肺癌（NSCLC）细胞中的蛋白质合成，在mTORC 1的下游起作用。OTUD 6 B与蛋白质合成起始复合物结合并修饰48 S前起始复合物的组分。两种主要的OTUD 6 B剪接同种型似乎以相反的方式调节蛋白质合成：长的OTUD 6 B-1同种型是抑制性的，而短的OTUD 6 B-2同种型刺激蛋白质合成。这些特性影响NSCLC细胞增殖，因为OTUD 6 B-1抑制DNA合成，而OTUD 6 B-2促进DNA合成。突变分析和下游介质表明，两种OTUD 6 B亚型修饰不同的细胞靶点。OTUD 6 B-2通过促进细胞周期蛋白D1的翻译，同时（直接或间接）调节c-Myc蛋白的稳定性来影响细胞周期蛋白D1的表达。这种现象似乎具有临床相关性，因为与正常样品相比，NSCLC细胞和人肿瘤样品具有降低的OTUD 6 B-1/OTUD 6 B-2 mRNA比率。总体OTUD 6 B表达水平在非肿瘤性和恶性组织之间没有显著变化，表明在转化过程中剪接因子的修饰是这种同种型转换的原因。由于蛋白质合成抑制是NSCLC的可行治疗策略，因此这些数据表明，与NSCLC生长特异性相关的OTUD 6 B亚型2代表了一种有吸引力的新型治疗靶标和用于恶性NSCLC早期诊断的潜在生物标志物。
Deubiquitinases (DUBs) are increasingly linked to the regulation of fundamental processes in normal and cancer cells, including DNA replication and repair, programmed cell death, and oncogenes and tumor suppressors signaling. Here evidence is presented that the deubiquitinase OTUD6B regulates protein synthesis in non-small cell lung cancer (NSCLC) cells, operating downstream from mTORC1. OTUD6B associates with the protein synthesis initiation complex and modifies components of the 48S preinitiation complex. The two main OTUD6B splicing isoforms seem to regulate protein synthesis in opposing fashions: the long OTUD6B-1 isoform is inhibitory, while the short OTUD6B-2 isoform stimulates protein synthesis. These properties affect NSCLC cell proliferation, since OTUD6B-1 represses DNA synthesis while OTUD6B-2 promotes it. Mutational analysis and downstream mediators suggest that the two OTUD6B isoforms modify different cellular targets. OTUD6B-2 influences the expression of cyclin D1 by promoting its translation while regulating (directly or indirectly) c-Myc protein stability. This phenomenon appears to have clinical relevance as NSCLC cells and human tumor specimens have a reduced OTUD6B-1/OTUD6B-2 mRNA ratio compared to normal samples. The global OTUD6B expression level does not change significantly between non-neoplastic and malignant tissues, suggesting that modifications of splicing factors during the process of transformation are responsible for this isoform switch. Because protein synthesis inhibition is a viable treatment strategy for NSCLC, these data indicate that OTUD6B isoform 2, being specifically linked to NSCLC growth, represents an attractive, novel therapeutic target and potential biomarker for early diagnosis of malignant NSCLC.