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OTUB1去泛素化酶促进前列腺癌细胞的体外侵袭和体内肿瘤发生。

OTUB1 de-ubiquitinating enzyme promotes prostate cancer cell invasion in vitro and tumorigenesis in vivo.

作者信息

Iglesias-Gato Diego, Chuan Yin-Choy, Jiang Ning, Svensson Charlotte, Bao Jing, Paul Indranil, Egevad Lars, Kessler Benedikt M, Wikström Pernilla, Niu Yuanjie, Flores-Morales Amilcar

机构信息

The Novo Nordisk Foundation Center for Protein Research, Faculty of Health Sciences, University of Copenhagen, 2200, Copenhagen, Denmark.

Tianjin Institute of Urology, Tianjin Medical University, 300211, Tianjin, China.

出版信息

Mol Cancer. 2015 Jan 27;14(1):8. doi: 10.1186/s12943-014-0280-2.

DOI:10.1186/s12943-014-0280-2
PMID:25623341
原文链接:https://pmc.ncbi.nlm.nih.gov/articles/PMC4320819/
Abstract

BACKGROUND

Ubiquitination is a highly dynamic and reversible process with a central role in cell homeostasis. Deregulation of several deubiquitinating enzymes has been linked to tumor development but their specific role in prostate cancer progression remains unexplored.

METHODS

RNAi screening was used to investigate the role of the ovarian tumor proteases (OTU) family of deubiquitinating enzymes on the proliferation and invasion capacity of prostate cancer cells. RhoA activity was measured in relation with OTUB1 effects on prostate cancer cell invasion. Tumor xenograft mouse model with stable OTUB1 knockdown was used to investigate OTUB1 influence in tumor growth.

RESULTS

Our RNAi screening identified OTUB1 as an important regulator of prostate cancer cell invasion through the modulation of RhoA activation. The effect of OTUB1 on RhoA activation is important for androgen-induced repression of p53 expression in prostate cancer cells. In localized prostate cancer tumors OTUB1 was found overexpressed as compared to normal prostatic epithelial cells. Prostate cancer xenografts expressing reduced levels of OTUB1 exhibit reduced tumor growth and reduced metastatic dissemination in vivo.

CONCLUSIONS

OTUB1 mediates prostate cancer cell invasion through RhoA activation and promotes tumorigenesis in vivo. Our results suggest that drugs targeting the catalytic activity of OTUB1 could potentially be used as therapeutics for metastatic prostate cancer.

摘要

背景

泛素化是一个高度动态且可逆的过程，在细胞稳态中起核心作用。几种去泛素化酶的失调与肿瘤发展有关，但其在前列腺癌进展中的具体作用仍未被探索。

方法

采用RNA干扰筛选来研究去泛素化酶的卵巢肿瘤蛋白酶（OTU）家族对前列腺癌细胞增殖和侵袭能力的作用。测量RhoA活性与OTUB1对前列腺癌细胞侵袭的影响之间的关系。使用稳定敲低OTUB1的肿瘤异种移植小鼠模型来研究OTUB1对肿瘤生长的影响。

结果

我们的RNA干扰筛选确定OTUB1是通过调节RhoA激活来调控前列腺癌细胞侵袭的重要因子。OTUB1对RhoA激活的作用对于雄激素诱导的前列腺癌细胞中p53表达的抑制很重要。在局限性前列腺癌肿瘤中，与正常前列腺上皮细胞相比，发现OTUB1过表达。表达降低水平OTUB1的前列腺癌异种移植瘤在体内表现出肿瘤生长减少和转移扩散减少。

结论

OTUB1通过RhoA激活介导前列腺癌细胞侵袭并促进体内肿瘤发生。我们的结果表明，靶向OTUB1催化活性的药物可能潜在地用作转移性前列腺癌的治疗药物。

https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d3/4320819/8761fadb7eea/12943_2014_280_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d3/4320819/b6512a43e6d5/12943_2014_280_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d3/4320819/079a7451d39f/12943_2014_280_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d3/4320819/e794708d281c/12943_2014_280_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d3/4320819/c3e9fd834075/12943_2014_280_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d3/4320819/8761fadb7eea/12943_2014_280_Fig5_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d3/4320819/b6512a43e6d5/12943_2014_280_Fig1_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d3/4320819/079a7451d39f/12943_2014_280_Fig2_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d3/4320819/e794708d281c/12943_2014_280_Fig3_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d3/4320819/c3e9fd834075/12943_2014_280_Fig4_HTML.jpg
https://cdn.ncbi.nlm.nih.gov/pmc/blobs/d7d3/4320819/8761fadb7eea/12943_2014_280_Fig5_HTML.jpg

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Colon cancer bears overexpression of OTUB1.结肠癌中OTUB1呈过表达。
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A putative OTU domain-containing protein 1 deubiquitinating enzyme is differentially expressed in thyroid cancer and identifies less-aggressive tumours.
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