Skip to main content
Key Specialties
Cardiology Diabetology Endocrinology Gastroenterology Geriatrics and Gerontology Gynecology and Obstetrics Hematology Infectious Disease Internal Medicine Nephrology Neurology Oncology Pediatrics Respiratory Medicine Rheumatology Surgery
Congress Coverage
2024 ACC Congress 2023 ESMO Congress 2023 EASD Congress 2023 ERS Congress 2023 ESC Congress
Clinical Collections
Advances in Alzheimer’s

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.
ADVANCED SEARCH
Log in
Top
Molecular Cancer
Published in: Molecular Cancer 1/2015

Open Access 01-12-2015 | Research

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

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

Published in: Molecular Cancer | Issue 1/2015

Login to get access

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.
Appendix
Available only for authorised users
Literature
1.
Crawford ED. Understanding the epidemiology, natural history, and key pathways involved in prostate cancer. Urology. 2009;73:S4–10.CrossRefPubMed
2.
3.
Chuan YC, Pang ST, Cedazo-Minguez A, Norstedt G, Pousette A, Flores-Morales A. Androgen induction of prostate cancer cell invasion is mediated by ezrin. J Biol Chem. 2006;281:29938–48.CrossRefPubMed
4.
Sun J, Liu W, Adams TS, Sun J, Li X, Turner AR, et al. DNA copy number alterations in prostate cancers: a combined analysis of published CGH studies. Prostate. 2007;67:692–700.CrossRefPubMed
5.
Gioeli D, Ficarro SB, Kwiek JJ, Aaronson D, Hancock M, Catling AD, et al. Androgen receptor phosphorylation: regulation and identification of the phosphorylation sites. J Biol Chem. 2002;277:29304–14.CrossRefPubMed
6.
Hu R, Isaacs WB, Luo J. A snapshot of the expression signature of androgen receptor splicing variants and their distinctive transcriptional activities. Prostate. 2011;71:1656–67.CrossRefPubMedCentralPubMed
7.
Steinkamp MP, O'Mahony OA, Brogley M, Rehman H, Lapensee EW, Dhanasekaran S, et al. Treatment-dependent androgen receptor mutations in prostate cancer exploit multiple mechanisms to evade therapy. Cancer Res. 2009;69:4434–42.CrossRefPubMedCentralPubMed
8.
Visakorpi T, Hyytinen E, Koivisto P, Tanner M, Keinanen R, Palmberg C, et al. In vivo amplification of the androgen receptor gene and progression of human prostate cancer. Nat Genet. 1995;9:401–6.CrossRefPubMed
9.
Wallen MJ, Linja M, Kaartinen K, Schleutker J, Visakorpi T. Androgen receptor gene mutations in hormone-refractory prostate cancer. J Pathol. 1999;189:559–63.CrossRefPubMed
10.
Waltering KK, Helenius MA, Sahu B, Manni V, Linja MJ, Janne OA, et al. Increased expression of androgen receptor sensitizes prostate cancer cells to low levels of androgens. Cancer Res. 2009;69:8141–9.CrossRefPubMed
11.
Chuan YC, Iglesias-Gato D, Fernandez-Perez L, Cedazo-Minguez A, Pang ST, Norstedt G, et al. Ezrin mediates c-Myc actions in prostate cancer cell invasion. Oncogene. 2010;29:1531–42.CrossRefPubMed
12.
13.
Komander D, Clague MJ, Urbe S. Breaking the chains: structure and function of the deubiquitinases. Nat Rev Mol Cell Biol. 2009;10:550–63.CrossRefPubMed
14.
Kato K, Nakajima K, Ui A, Muto-Terao Y, Ogiwara H, Nakada S. Fine-tuning of DNA damage-dependent ubiquitination by OTUB2 supports the DNA repair pathway choice. Mol Cell. 2014;53:617–30.CrossRefPubMed
15.
Nakada S, Tai I, Panier S, Al-Hakim A, Iemura S, Juang YC, et al. Non-canonical inhibition of DNA damage-dependent ubiquitination by OTUB1. Nature. 2010;466:941–6.CrossRefPubMed
16.
Liu X, Jiang WN, Wang JG, Chen H. Colon cancer bears overexpression of OTUB1. Pathol Res Pract. 2014;210:770–3.CrossRefPubMed
17.
Pujari R, Hunte R, Khan WN, Shembade N. A20-mediated negative regulation of canonical NF-kappaB signaling pathway. Immunol Res. 2013;57:166–71.CrossRefPubMed
18.
Carneiro AP, Reis CF, Morari EC, Maia YC, Nascimento R, Bonatto JM, et al. A putative OTU domain-containing protein 1 deubiquitinating enzyme is differentially expressed in thyroid cancer and identifies less-aggressive tumours. Br J Cancer. 2014;111:551–8.CrossRefPubMed
19.
Mevissen TE, Hospenthal MK, Geurink PP, Elliott PR, Akutsu M, Arnaudo N, et al. OTU deubiquitinases reveal mechanisms of linkage specificity and enable ubiquitin chain restriction analysis. Cell. 2013;154:169–84.CrossRefPubMedCentralPubMed
20.
Fiil BK, Damgaard RB, Wagner SA, Keusekotten K, Fritsch M, Bekker-Jensen S, et al. OTULIN restricts Met1-linked ubiquitination to control innate immune signaling. Mol Cell. 2013;50:818–30.CrossRefPubMedCentralPubMed
21.
Wiener R, DiBello AT, Lombardi PM, Guzzo CM, Zhang X, Matunis MJ, et al. E2 ubiquitin-conjugating enzymes regulate the deubiquitinating activity of OTUB1. Nat Struct Mol Biol. 2013;20:1033–9.CrossRefPubMedCentralPubMed
22.
Edelmann MJ, Iphofer A, Akutsu M, Altun M, di Gleria K, Kramer HB, et al. Structural basis and specificity of human otubain 1-mediated deubiquitination. Biochem J. 2009;418:379–90.CrossRefPubMed
23.
Blagoev B, Mann M. Quantitative proteomics to study mitogen-activated protein kinases. Methods. 2006;40:243–50.CrossRefPubMed
24.
25.
Lin MF, Garcia-Arenas R, Chao YC, Lai MM, Patel PC, Xia XZ. Regulation of prostatic acid phosphatase expression and secretion by androgen in LNCaP human prostate carcinoma cells. Arch Biochem Biophys. 1993;300:384–90.CrossRefPubMed
26.
Zhao JC, Yu J, Runkle C, Wu L, Hu M, Wu D, et al. Cooperation between Polycomb and androgen receptor during oncogenic transformation. Genome Res. 2012;22:322–31.CrossRefPubMedCentralPubMed
27.
Edelmann MJ, Kramer HB, Altun M, Kessler BM. Post-translational modification of the deubiquitinating enzyme otubain 1 modulates active RhoA levels and susceptibility to Yersinia invasion. FEBS J. 2010;277:2515–30.CrossRefPubMed
28.
Gadea G, de Toledo M, Anguille C, Roux P. Loss of p53 promotes RhoA-ROCK-dependent cell migration and invasion in 3D matrices. J Cell Biol. 2007;178:23–30.CrossRefPubMedCentralPubMed
29.
Bremm A, Freund SM, Komander D. Lys11-linked ubiquitin chains adopt compact conformations and are preferentially hydrolyzed by the deubiquitinase Cezanne. Nat Struct Mol Biol. 2010;17:939–47.CrossRefPubMedCentralPubMed
30.
31.
Licchesi JD, Mieszczanek J, Mevissen TE, Rutherford TJ, Akutsu M, Virdee S, et al. An ankyrin-repeat ubiquitin-binding domain determines TRABID's specificity for atypical ubiquitin chains. Nat Struct Mol Biol. 2012;19:62–71.CrossRef
32.
33.
34.
Stanisic V, Malovannaya A, Qin J, Lonard DM, O'Malley BW. OTU Domain-containing ubiquitin aldehyde-binding protein 1 (OTUB1) deubiquitinates estrogen receptor (ER) alpha and affects ERalpha transcriptional activity. J Biol Chem. 2009;284:16135–45.CrossRefPubMedCentralPubMed
35.
Coutts AS, Weston L, La Thangue NB. Actin nucleation by a transcription co-factor that links cytoskeletal events with the p53 response. Cell Cycle. 2010;9:1511–5.CrossRefPubMed
36.
Coutts AS, Weston L, La Thangue NB. A transcription co-factor integrates cell adhesion and motility with the p53 response. Proc Natl Acad Sci U S A. 2009;106:19872–7.CrossRefPubMedCentralPubMed
37.
Gonzalez-Montelongo MC, Marin R, Perez JA, Gomez T, Diaz M. Polyamines transduce the nongenomic, androgen-induced calcium sensitization in intestinal smooth muscle. Mol Endocrinol. 2013;27:1603–16.CrossRefPubMed
38.
Kluth M, Harasimowicz S, Burkhardt L, Grupp K, Krohn A, Prien K, et al. Clinical significance of different types of p53 gene alteration in surgically treated prostate cancer. International journal of cancer. Int J Cancer J Int Du Cancer. 2014;135:1369–80.CrossRef
39.
Coso OA, Chiariello M, Yu JC, Teramoto H, Crespo P, Xu N, et al. The small GTP-binding proteins Rac1 and Cdc42 regulate the activity of the JNK/SAPK signaling pathway. Cell. 1995;81:1137–46.CrossRefPubMed
40.
Schneider CA, Rasband WS, Eliceiri KW. NIH Image to ImageJ: 25 years of image analysis. Nat Methods. 2012;9:671–5.CrossRefPubMed
41.
Hammarsten P, Karalija A, Josefsson A, Rudolfsson SH, Wikstrom P, Egevad L, et al. Low levels of phosphorylated epidermal growth factor receptor in nonmalignant and malignant prostate tissue predict favorable outcome in prostate cancer patients. Clin Cancer Res. 2010;16:1245–55.CrossRefPubMed
42.
Cox J, Mann M. MaxQuant enables high peptide identification rates, individualized p.p.b.-range mass accuracies and proteome-wide protein quantification. Nat Biotechnol. 2008;26:1367–72.CrossRefPubMed
43.
Cox J, Neuhauser N, Michalski A, Scheltema RA, Olsen JV, Mann M. Andromeda: a peptide search engine integrated into the MaxQuant environment. J Proteome Res. 2011;10:1794–805.CrossRefPubMed
44.
Niu Y, Altuwaijri S, Yeh S, Lai KP, Yu S, Chuang KH, et al. Targeting the stromal androgen receptor in primary prostate tumors at earlier stages. Proc Natl Acad Sci U S A. 2008;105:12188–93.CrossRefPubMedCentralPubMed
45.
Jing C, Ning J, Yuanjie N. The preventative effects of sunitinib malate observed in the course from non-castration to castration LNCaP xenograft prostate tumors. J Cancer Res Clin Oncol. 2012;138:2137–43.CrossRefPubMed
46.
Jiang N, Hjorth-Jensen K, Hekmat O, Iglesias-Gato D, Kruse T, Wang C, et al. In vivo quantitative phosphoproteomic profiling identifies novel regulators of castration-resistant prostate cancer growth. Oncogene. 2014. [Epub ahead of print]
47.
Taylor BS, Schultz N, Hieronymus H, Gopalan A, Xiao Y, Carver BS, et al. Integrative genomic profiling of human prostate cancer. Cancer Cell. 2010;18:11–22.CrossRefPubMedCentralPubMed
48.
Berenjeno IM, Nunez F, Bustelo XR. Transcriptomal profiling of the cellular transformation induced by Rho subfamily GTPases. Oncogene. 2007;26:4295–305.CrossRefPubMedCentralPubMed
Metadata
Title
OTUB1 de-ubiquitinating enzyme promotes prostate cancer cell invasion in vitro and tumorigenesis in vivo
Authors
Diego Iglesias-Gato
Yin-Choy Chuan
Ning Jiang
Charlotte Svensson
Jing Bao
Indranil Paul
Lars Egevad
Benedikt M Kessler
Pernilla Wikström
Yuanjie Niu
Amilcar Flores-Morales
Publication date
01-12-2015
Publisher
BioMed Central
Published in
Molecular Cancer / Issue 1/2015
Electronic ISSN: 1476-4598
DOI
https://doi.org/10.1186/s12943-014-0280-2

Other articles of this Issue 1/2015

Molecular Cancer 1/2015 Go to the issue

Research

The long noncoding RNA HOTAIR has tissue and cell type-dependent effects on HOX gene expression and phenotype of urothelial cancer cells

Review

The twisted survivin connection to angiogenesis

Reviewer acknowledgement

Thanking our 2014 peer reviewers

Research

Anticancer effect of tectochrysin in colon cancer cell via suppression of NF-kappaB activity and enhancement of death receptor expression

Research

Organometallic nucleosides induce non-classical leukemic cell death that is mitochondrial-ROS dependent and facilitated by TCL1-oncogene burden

Research

BCR/ABL1 and BCR are under the transcriptional control of the MYC oncogene
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine
Image Credits