USP33, a new player in lung cancer, mediates Slit-Robo signaling

Abstract

Ubiquitin specific protease 33 (USP33) is a multifunctional protein regulating diverse cellular processes. The expression and role ofUSP33 in lung cancer remain unexplored. In this study, we show that USP33 is down-regulated in multiple cohorts of lung cancer patients and that low expression of USP33 is associated with poor prognosis. USP33 mediates Slit-Robo signaling in lung cancer cell migration. Downregulation of USP33 reduces the protein stability of Robo1inlungcancer cells, providing apreviouslyunknown mechanism for USP33 function in mediating Slit activity in lung cancer cells. Taken together, USP33 is a new player in lung cancer that regulates Slit-Robo signaling. Our data suggest that USP33 may be a candidate tumor suppressor for lung cancer with potential as a prognostic marker.

Keywords

USP33 / Slit / Robo / lung cancer / Slit-Robo signaling / tumor suppressor / prognostic marker

References

[1] Ballard MS, Hinck L (2012) A roundabout way to cancer. Adv Cancer Res114: 187-235

[2] Bashaw GJ, Kidd T, Murray D, Pawson T, Goodman CS (2000) Repulsive axon guidance: Abelson and enabled play opposing roles downstream of the roundabout receptor. Cell101: 703-715

[3] Berthouze M, Venkataramanan V, Li Y, Shenoy SK (2009) The deubiquitinases USP33 and USP20 coordinate beta2 adrenergic receptor recycling and resensitization. EMBO J28: 1684-1696

[4] Biankin AV, Waddell N, Kassahn KS, Gingras MC, Muthuswamy LB, Johns AL, Miller DK, Wilson PJ, Patch AM, Wu J (2012) Pancreatic cancer genomes reveal aberrations in axon guidance pathway genes. Nature491: 399-405

[5] Brantley-Sieders DM, Dunaway CM, Rao M, Short S, Hwang Y, Gao Y, Li D, Jiang A, Shyr Y, Wu JY (2011) Angiocrine factors modulate tumor proliferation and motility through EphA2 repression of Slit2 tumor suppressor function in endothelium. Cancer Res71: 976-987

[6] Brose K, Bland KS, Wang KH, Arnott D, Henzel W, Goodman CS, Tessier-Lavigne M, Kidd T (1999) Slit proteins bind Robo receptors and have an evolutionarily conserved role in repulsive axon guidance. Cell96: 795-806

[7] Buus R, Faronato M, Hammond DE, Urbe S, Clague MJ (2009) Deubiquitinase activities required for hepatocyte growth factorinduced scattering of epithelial cells. Curr Biol19: 1463-1466

[8] Chen J, Dexheimer TS, Ai Y, Liang Q, Villamil MA, Inglese J, Maloney DJ, Jadhav A, Simeonov A, Zhuang Z (2011) Selective and cell-active inhibitors of the USP1/ UAF1 deubiquitinase complex reverse cisplatin resistance in non-small cell lung cancer cells. Chem Biol18: 1390-1400

[9] Chen Y, Gao Y, Tian Y, Tian DL (2013) PRKACB is downregulated in non-small cell lung cancer and exogenous PRKACB inhibits proliferation and invasion of LTEP-A2 cells. Oncol Lett5: 1803-1808

[10] Ciechanover A, Schwartz AL (1994) The ubiquitin-mediated proteolytic pathway: mechanisms of recognition of the proteolytic substrate and involvement in the degradation of native cellular proteins. FASEB J8: 182-191

[11] Cooper WA, Lam DC, O’Toole SA, Minna JD (2013) Molecular biology of lung cancer. J Thorac Dis5(Suppl 5): S479-S490

[12] Curcio-Morelli C, Zavacki AM, Christofollete M, Gereben B, de Freitas BC, Harney JW, Li Z, Wu G, Bianco AC (2003) Deubiquitination of type 2 iodothyronine deiodinase by von Hippel-Lindau protein-interacting deubiquitinating enzymes regulates thyroid hormone activation. J Clin Invest112: 189-196

[13] Dallol A, Da Silva NF, Viacava P, Minna JD, Bieche I, Maher ER, Latif F (2002) SLIT2, a human homologue of the Drosophila Slit2 gene, has tumor suppressor activity and is frequently inactivated in lung and breast cancers. Cancer Res62: 5874-5880

[14] Dallol A, Krex D, Hesson L, Eng C, Maher ER, Latif F (2003) Frequent epigenetic inactivation of the SLIT2 gene in gliomas. Oncogene22: 4611-4616

[15] Ferlay J, Shin HR, Bray F, Forman D, Mathers C, Parkin DM (2010) Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer127: 2893-2917

[16] Gao J, Aksoy BA, Dogrusoz U, Dresdner G, Gross B, Sumer SO, Sun Y, Jacobsen A, Sinha R, Larsson E (2013) Integrative analysis of complex cancer genomics and clinical proflles using the cBioPortal. Sci Signal6: pl1

[17] Girard L, Zochbauer-Muller S, Virmani AK, Gazdar AF, Minna JD (2000) Genome-wide allelotyping of lung cancer identifles new regions of allelic loss, differences between small cell lung cancer and non-small cell lung cancer, and loci clustering. Cancer Res60: 4894-4906

[18] Gyorffy B, Lanczky A, Eklund AC, Denkert C, Budczies J, Li Q, Szallasi Z (2010) An online survival analysis tool to rapidly assess the effect of 22,277 genes on breast cancer prognosis using microarray data of 1,809 patients. Breast Cancer Res Treat123: 725-731

[19] Gyorffy B, Surowiak P, Budczies J, Lanczky A (2013) Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PloS One8: e82241

[20] Herbst RS, Heymach JV, Lippman SM (2008) Molecular origins of caner: lung cancer. N Engl J Med359: 1367-1380

[21] Kim HS, Mendiratta S, Kim J, Pecot CV, Larsen JE, Zubovych I, Seo BY, Eskiocak B, Chung H, McMillan E (2013) Systematic identiflcation of molecular subtype-selective vulnerabilities in non-small-cell lung cancer. Cell155: 552-566

[22] Li HS, Chen JH, Wu W, Fagaly T, Zhou L, Yuan W, Dupuis S, Jiang ZH, Nash W, Gick C (1999) Vertebrate slit, a secreted ligand for the transmembrane protein roundabout, is a repellent for olfactory bulb axons. Cell96: 807-818

[23] Li Z, Wang D, Na X, Schoen SR, Messing EM, Wu G (2002) Identiflcation of a deubiquitinating enzyme subfamily as substrates of the von Hippel-Lindau tumor suppressor. Biochem Biophys Res Commun294: 700-709

[24] Li J, D’Angiolella V, Seeley ES, Kim S, Kobayashi T, Fu W, Campos EI, Pagano M, Dynlacht BD (2013) USP33 regulates centrosome biogenesis via deubiquitination of the centriolar protein CP110. Nature495: 255-259

[25] Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A, Chinnaiyan AM (2004) ONCOMINE: a cancer microarray database and integrated data-mining platform. Neoplasia6: 1-6

[26] Rothberg JM, Hartley DA, Walther Z, Artavanis-Tsakonas S (1988) Slit: an EGF-homologous locus of D. melanogaster involved in the development of the embryonic central nervous system. Cell55: 1047-1059

[27] Sanborn JZ, Benz SC, Craft B, Szeto C, Kober KM, Meyer L, Vaske CJ, Goldman M, Smith KE, Kuhn RM (2011) The UCSC cancer genomics browser: update 2011. Nucleic Acids Res39: D951-D959

[28] Shenoy SK, Modi AS, Shukla AK, Xiao K, Berthouze M, Ahn S, Wilkinson KD, Miller WE, Lefkowitz RJ (2009) Beta-arrestindependent signaling and trafflcking of 7-transmembrane receptors is reciprocally regulated by the deubiquitinase USP33 and the E3 ligase Mdm2. Proc Natl Acad Sci USA106: 6650-6655

[29] Simpson JH, Bland KS, Fetter RD, Goodman CS (2000) Short-range and long-range guidance by Slit and its Robo receptors: a combinatorial code of Robo receptors controls lateral position. Cell103: 1019-1032

[30] Tie J, Pan Y, Zhao L, Wu K, Liu J, Sun S, Guo X, Wang B, Gang Y, Zhang Y, Li Q, Qiao T, Zhao Q, Nie Y, Fan D (2010) MiR-218 inhibits invasion and metastasis of gastric cancer by targeting the Robo1 receptor. PLoS Genet6( 3): e1000879

[31] Tsai MF, Wang CC, Chang GC, Chen CY, Chen HY, Cheng CL, Yang YP, Wu CY, Shih FY, Liu CC (2006) A new tumor suppressor DnaJ-like heat shock protein, HLJ1, and survival of patients with non-small-cell lung carcinoma. J Natl Cancer Inst98: 825-838

[32] Tseng RC, Lee SH, Hsu HS, Chen BH, Tsai WC, Tzao C, Wang YC (2010) SLIT2 attenuation during lung cancer progression deregulates beta-catenin and E-cadherin and associates with poor prognosis. Cancer Res70: 543-551

[33] Ventii KH, Devi NS, Friedrich KL, Chernova TA, Tighiouart M, Van Meir EG, Wilkinson KD (2008) BRCA1-associated protein-1 is a tumor suppressor that requires deubiquitinating activity and nuclear localization. Cancer Res68: 6953-6962

[34] Wu W, Wong K, Chen J, Jiang Z, Dupuis S, Wu JY, Rao Y (1999) Directional guidance of neuronal migration in the olfactory system by the protein Slit. Nature400: 331-336

[35] Wu JY, Feng L, Park HT, Havlioglu N, Wen L, Tang H, Bacon KB, Jiang Z, Zhang X, Rao Y (2001) The neuronal repellent Slit inhibits leukocyte chemotaxis induced by chemotactic factors. Nature410: 948-952

[36] Xian J, Clark KJ, Fordham R, Pannell R, Rabbitts TH, Rabbitts PH (2001) Inadequate lung development and bronchial hyperplasia in mice with a targeted deletion in the Dutt1/Robo1 gene. Proc Natl Acad Sci USA98: 15062-15066

[37] Yuasa-Kawada J, Kinoshita-Kawada M, Rao Y, Wu JY (2009a) Deubiquitinating enzyme USP33/VDU1 is required for Slit signaling in inhibiting breast cancer cell migration. Proc Natl Acad Sci USA106: 14530-14535

[38] Yuasa-Kawada J, Kinoshita-Kawada M, Wu G, Rao Y, Wu JY (2009b) Midline crossing and Slit responsiveness of commissural axons require USP33. Nat Neurosci12: 1087-1089

[39] Zhang Y, Foreman O, Wigle DA, Kosari F, Vasmatzis G, Salisbury JL, van Deursen J, Galardy PJ (2012) USP44 regulates centrosome positioning to prevent aneuploidy and suppress tumorigenesis. J Clin Invest122: 4362-4374

[40] Zhu J, Sanborn JZ, Benz S, Szeto C, Hsu F, Kuhn RM, Karolchik D, Archie J, Lenburg ME, Esserman LJ (2009) The UCSC cancer genomics browser. Nat Methods6: 239-240

RIGHTS & PERMISSIONS

This is an open-access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.