RANBP9 and RANBP10 cooperate in regulating non-small cell lung cancer proliferation.

IF 12.8 1区 医学 Q1 ONCOLOGY
Arturo Orlacchio, Yasuko Kajimura, Lara Rizzotto, Anna Tessari, Shimaa H A Soliman, Rosa Visone, Liwen Zhang, Brian Fries, Lino Tessarollo, Joseph Amann, David P Carbone, Alessia Lodi, Amer Ahmed, Ruggiero Gorgoglione, Giuseppe Fiermonte, Mike Freitas, Dario Palmieri, Jacob Kaufman, Vincenzo Coppola
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引用次数: 0

Abstract

Background: RANBP9 and RANBP10, also called Scorpins, are essential components of the C-terminal to LisH (CTLH) complex, an evolutionarily conserved poorly investigated multisubunit E3 ligase. Their role in non-small cell lung cancer (NSCLC) is unknown.

Methods: In this study, first we used stable loss-of function and overexpression inducible cell lines to investigate the ability of either RANBP9 or RANBP10 to form their own functional CTLH complex. Then, we probed lysates from patient tumors and analyzed data from publicly available repositories to investigate the expression of RANBP9 and RANBP10. Finally, we used inducible cell lines in vitro to recapitulate the expression observed in patients and investigate the changes of the proteome and the ubiquitylome associated with either RANBP9 or RANBP10 in NSCLC.

Results: Here, we show that the two Scorpins are both expressed in NSCLC cells and that either of them can independently support the formation of the CTLH complex. Short-term experiments revealed that the RANBP9 and RANBP10 proteins balance each other in terms of expression, and the acute overexpression of one or the other results in significant reshaping of the NSCLC cell proteome and ubiquitylome. A higher RANBP9/RANBP10 ratio is associated with greater proliferation in both NSCLC cell lines and patients. Acute increased expression of RANBP10 slows NSCLC cell proliferation and decreases the level of proliferation-associated proteins, including key players in DNA replication.

Conclusions: We present evidence that the Scorpins act as partial antagonists and work together as one sophisticated rheostat to modulate the CTLH complex ubiquitylation output, which regulates cell proliferation and other key biological processes in NSCLC. These results suggest that the two Scorpins can be considered as targets for the treatment of NSCLC.

RANBP9和RANBP10协同调节非小细胞肺癌的增殖。
背景:RANBP9和RANBP10,也被称为Scorpins,是c -末端到LisH (CTLH)复合体的重要组成部分,这是一种进化上保守的多亚基E3连接酶,研究很少。它们在非小细胞肺癌(NSCLC)中的作用尚不清楚。方法:在本研究中,我们首先使用稳定功能缺失和过表达诱导细胞系来研究RANBP9或RANBP10形成自身功能性CTLH复合物的能力。然后,我们检测了患者肿瘤的裂解物,并分析了公开可用数据库的数据,以研究RANBP9和RANBP10的表达。最后,我们利用体外诱导细胞系概括了在患者中观察到的表达,并研究了与RANBP9或RANBP10相关的蛋白质组和泛素组在NSCLC中的变化。结果:我们发现这两种Scorpins都在NSCLC细胞中表达,并且它们中的任何一种都可以独立支持CTLH复合物的形成。短期实验显示,RANBP9和RANBP10蛋白在表达上相互平衡,其中一个蛋白的急性过表达会导致NSCLC细胞蛋白质组和泛素组的显著重塑。在NSCLC细胞系和患者中,较高的RANBP9/RANBP10比值与更高的增殖有关。RANBP10的急性表达增加减缓了NSCLC细胞的增殖,并降低了增殖相关蛋白的水平,包括DNA复制的关键参与者。结论:我们提供的证据表明,Scorpins作为部分拮抗剂,共同作为一个复杂的变阻器调节CTLH复合物泛素化的输出,从而调节非小细胞肺癌的细胞增殖和其他关键的生物学过程。上述结果提示,这两种Scorpins可作为治疗非小细胞肺癌的靶点。
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来源期刊
CiteScore
18.20
自引率
1.80%
发文量
333
审稿时长
1 months
期刊介绍: The Journal of Experimental & Clinical Cancer Research is an esteemed peer-reviewed publication that focuses on cancer research, encompassing everything from fundamental discoveries to practical applications. We welcome submissions that showcase groundbreaking advancements in the field of cancer research, especially those that bridge the gap between laboratory findings and clinical implementation. Our goal is to foster a deeper understanding of cancer, improve prevention and detection strategies, facilitate accurate diagnosis, and enhance treatment options. We are particularly interested in manuscripts that shed light on the mechanisms behind the development and progression of cancer, including metastasis. Additionally, we encourage submissions that explore molecular alterations or biomarkers that can help predict the efficacy of different treatments or identify drug resistance. Translational research related to targeted therapies, personalized medicine, tumor immunotherapy, and innovative approaches applicable to clinical investigations are also of great interest to us. We provide a platform for the dissemination of large-scale molecular characterizations of human tumors and encourage researchers to share their insights, discoveries, and methodologies with the wider scientific community. By publishing high-quality research articles, reviews, and commentaries, the Journal of Experimental & Clinical Cancer Research strives to contribute to the continuous improvement of cancer care and make a meaningful impact on patients' lives.
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