Generic placeholder image

Anti-Cancer Agents in Medicinal Chemistry

Editor-in-Chief

ISSN (Print): 1871-5206
ISSN (Online): 1875-5992

Review Article

The Emerging Role of CSN6 in Biological Behavior and Cancer Progress

Author(s): Zun Mao, Cheng Chen and Dong-Sheng Pei*

Volume 19, Issue 10, 2019

Page: [1198 - 1204] Pages: 7

DOI: 10.2174/1871520619666190408142131

Price: $65

Abstract

Background: The Constitutive Photomorphogenesis 9 (COP9) signalosome (CSN) subunit 6 (CSN6) noticeably acts as a regulator of the degradation of cancer-related proteins, which contributes to cancerogenesis. The aims of this paper are to expound the research advances of CSN6, particularly focusing on roles of CSN6 in the regulation of biological behavior and cancer progress.

Methods: Literature from PubMed and Web of Science databases about biological characteristics and application of CSN6 published in recent years was collected to conduct a review.

Results: CSN6, not only the non-catalytic Mpr1p and Pad1p N-terminal (MPN) subunit of CSN, but also a relatively independent protein molecule, has received great attention as a regulator of a wide range of developmental processes by taking part in the ubiquitin-proteasome system and signal transduction, as well as regulating genome integrity and DNA damage response. In addition, phosphorylation of CSN6 increases the stability of CSN6, thereby promoting its regulatory capacity. Moreover, CSN6 is overexpressed in many types of cancer compared with normal tissues and is involved in the regulation of several important intracellular pathways, consisting of cell proliferation, migration, invasion, transformation, and tumorigenesis.

Conclusion: We mainly present insights into the function and research development of CSN6, hoping that it can help guide the treatment of developmental defects and improve clinical care, especially in the regulation of cancer signaling pathways.

Keywords: CSN, CSN6, ubiquitination, protein degradation, cancer, tumorigenesis.

Graphical Abstract
[1]
Wei, N.; Chamovitz, D.A.; Deng, X.W. Arabidopsis COP9 is a component of a novel signaling complex mediating light control of development. Cell, 1994, 78, 117-124.
[2]
Zhang, S.N.; Pei, D.S.; Zheng, J.N. The COP9 signalosome subunit 6 (CSN6): A potential oncogene. Cell Div., 2013, 8, 14.
[3]
Li, P.; Xie, L.; Gu, Y.; Li, J.; Xie, J. Roles of multifunctional COP9 Signalosome complex in cell fate and implications for drug discovery. J. Cell. Physiol., 2017, 232, 1246-1253.
[4]
Xiao, D.; Yang, S.; Huang, L.; He, H.; Pan, H.; He, J. COP9 signalosome subunit CSN5, but not CSN6, is upregulated in lung adenocarcinoma and predicts poor prognosis. J. Thorac. Dis., 2018, 10, 1596-1606.
[5]
Glickman, M.H.; Rubin, D.M.; Coux, O.; Wefes, I.; Pfeifer, G.; Cjeka, Z.; Baumeister, W.; Fried, V.A.; Finley, D. A subcomplex of the proteasome regulatory particle required for ubiquitin-conjugate degradation and related to the COP9-signalosome and eIF3. Cell, 1998, 94, 615-623.
[6]
Aravind, L.; Ponting, C.P. Homologues of 26S proteasome subunits are regulators of transcription and translation. Protein Sci., 1998, 7, 1250-1254.
[7]
Hofmann, K.; Bucher, P. The PCI domain: A common theme in three multiprotein complexes. Trends Biochem. Sci., 1998, 23, 204-205.
[8]
Gusmaroli, G.; Figueroa, P.; Serino, G.; Deng, X.W. Role of the MPN subunits in COP9 signalosome assembly and activity, and their regulatory interaction with Arabidopsis Cullin3-based E3 ligases. Plant Cell, 2007, 19, 564-581.
[9]
Pick, E.; Golan, A.; Zimbler, J.Z.; Guo, L.; Sharaby, Y.; Tsuge, T.; Hofmann, K.; Wei, N. The minimal deneddylase core of the COP9 signalosome excludes the Csn6 MPN- domain. PLoS One, 2012, 7e43980
[10]
Braus, G.H.; Irniger, S.; Bayram, O. Fungal development and the COP9 signalosome. Curr. Opin. Microbiol., 2010, 13, 672-676.
[11]
Rozen, S.; Fuzesi-Levi, M.G.; Ben-Nissan, G.; Mizrachi, L.; Gabashvili, A.; Levin, Y.; Ben-Dor, S.; Eisenstein, M.; Sharon, M. CSNAP is a stoichiometric subunit of the COP9 signalosome. Cell Rep., 2015, 13, 585-598.
[12]
Stone, S.L. The role of ubiquitin and the 26S proteasome in plant abiotic stress signaling. Front. Plant Sci., 2014, 5, 135.
[13]
Yang, L.; Chen, J.; Huang, X.; Zhang, E.; He, J.; Cai, Z. Novel insights into E3 ubiquitin ligase in cancer chemoresistance. Am. J. Med. Sci., 2018, 355, 368-376.
[14]
Wenzel, D.M.; Klevit, R.E. Following Ariadne’s thread: A new perspective on RBR ubiquitin ligases. BMC Biol., 2012, 10, 24.
[15]
Wang, D.; Ma, L.; Wang, B.; Liu, J.; Wei, W. E3 ubiquitin ligases in cancer and implications for therapies. Cancer Metastasis Rev., 2017, 36, 683-702.
[16]
Wang, L.; Zheng, J.N.; Pei, D.S. The emerging roles of Jab1/CSN5 in cancer. Med. Oncol (Northwood, London, England), 2016, 33, 90.
[17]
Kandala, S.; Kim, I.M.; Su, H. Neddylation and deneddylation in cardiac biology. Am. J. Cardiovasc. Dis., 2014, 4, 140-158.
[18]
Cope, G.A.; Suh, G.S.; Aravind, L.; Schwarz, S.E.; Zipursky, S.L.; Koonin, E.V.; Deshaies, R.J. Role of predicted metalloprotease motif of Jab1/Csn5 in cleavage of Nedd8 from Cul1. Science (New York, N.Y.), 2002, 298, 608-611.
[19]
Schwechheimer, C.; Serino, G.; Callis, J.; Crosby, W.L.; Lyapina, S.; Deshaies, R.J.; Gray, W.M.; Estelle, M.; Deng, X.W. Interactions of the COP9 signalosome with the E3 ubiquitin ligase SCFTIRI in mediating auxin response. Science (New York, N.Y.), 2001, 292, 1379-1382.
[20]
Lingaraju, G.M.; Bunker, R.D.; Cavadini, S.; Hess, D.; Hassiepen, U.; Renatus, M.; Fischer, E.S.; Thoma, N.H. Crystal structure of the human COP9 signalosome. Nature, 2014, 512, 161-165.
[21]
Chen, J.; Shin, J.H.; Zhao, R.; Phan, L.; Wang, H.; Xue, Y.; Post, S.M.; Ho Choi, H.; Chen, J.S.; Wang, E.; Zhou, Z.; Tseng, C.; Gully, C.; Velazquez-Torres, G.; Fuentes-Mattei, E.; Yeung, G.; Qiao, Y.; Chou, P.C.; Su, C.H.; Hsieh, Y.C.; Hsu, S.L.; Ohshiro, K.; Shaikenov, T.; Wang, H.; Yeung, S.C.; Lee, M.H. CSN6 drives carcinogenesis by positively regulating Myc stability. Nat. Commun., 2014, 5, 5384.
[22]
Birol, M.; Enchev, R.I.; Padilla, A.; Stengel, F.; Aebersold, R.; Betzi, S.; Yang, Y.; Hoh, F.; Peter, M.; Dumas, C.; Echalier, A. Structural and biochemical characterization of the Cop9 signalosome CSN5/CSN6 heterodimer. PLoS One, 2014, 9e105688
[23]
Sanches, M.; Alves, B.S.; Zanchin, N.I.; Guimaraes, B.G. The crystal structure of the human Mov34 MPN domain reveals a metal-free dimer. J. Mol. Biol., 2007, 370, 846-855.
[24]
Ma, X.L.; Xu, M.; Jiang, T. Crystal structure of the human CSN6 MPN domain. Biochem. Biophys. Res. Commun., 2014, 453, 25-30.
[25]
Cavadini, S.; Fischer, E.S.; Bunker, R.D.; Potenza, A.; Lingaraju, G.M.; Goldie, K.N.; Mohamed, W.I.; Faty, M.; Petzold, G.; Beckwith, R.E.; Tichkule, R.B.; Hassiepen, U.; Abdulrahman, W.; Pantelic, R.S.; Matsumoto, S.; Sugasawa, K.; Stahlberg, H.; Thoma, N.H. Cullin-RING ubiquitin E3 ligase regulation by the COP9 signalosome. Nature, 2016, 531, 598-603.
[26]
Mosadeghi, R.; Reichermeier, K.M.; Winkler, M.; Schreiber, A.; Reitsma, J.M.; Zhang, Y.; Stengel, F.; Cao, J.; Kim, M.; Sweredoski, M.J.; Hess, S.; Leitner, A.; Aebersold, R.; Peter, M. Structural and kinetic analysis of the COP9-Signalosome activation and the cullin-RING ubiquitin ligase deneddylation cycle. eLife, 2016, 5e12102
[27]
Birol, M.; Echalier, A. Structure and function of MPN (Mpr1/Pad1 N-terminal) domain-containing proteins. Curr. Protein Pept. Sci., 2014, 15, 504-517.
[28]
Zhang, H.; Gao, Z.Q.; Wang, W.J.; Liu, G.F.; Shtykova, E.V.; Xu, J.H.; Li, L.F.; Su, X.D.; Dong, Y.H. The crystal structure of the MPN domain from the COP9 signalosome subunit CSN6. FEBS Lett., 2012, 586, 1147-1153.
[29]
Peng, Z.; Serino, G.; Deng, X.W. Molecular characterization of subunit 6 of the COP9 signalosome and its role in multifaceted developmental processes in Arabidopsis. Plant Cell, 2001, 13, 2393-2407.
[30]
Fang, L.; Lu, W.; Choi, H.H.; Yeung, S.C.; Tung, J.Y.; Hsiao, C.D.; Fuentes-Mattei, E.; Menter, D.; Chen, C.; Wang, L.; Wang, J.; Lee, M.H. ERK2-dependent phosphorylation of CSN6 is critical in colorectal cancer development. Cancer Cell, 2015, 28, 183-197.
[31]
Gao, S.; Fang, L.; Phan, L.M.; Qdaisat, A.; Yeung, S.C.; Lee, M.H. COP9 signalosome subunit 6 (CSN6) regulates E6AP/UBE3A in cervical cancer. Oncotarget, 2015, 6, 28026-28041.
[32]
Iyer, S.V.; Iwakuma, T. A novel link between the HER2-Akt and MDM2-p53 pathways via CSN6. Cell Cycle (Georgetown, Tex.), 2012, 11, 4112.
[33]
Xue, Y.; Chen, J.; Choi, H.H.; Phan, L.; Chou, P.C.; Zhao, R.; Yang, H.; Santiago, J.; Liu, M.; Yeung, G.E.; Yeung, S.C.; Lee, M.H. HER2-Akt signaling in regulating COP9 signalsome subunit 6 and p53. Cell Cycle (Georgetown, Tex.), 2012, 11, 4181-4190.
[34]
Deng, Q.; He, C.; Wu, Y.; Zhang, J.; Zhang, Y.; Wang, Z.; Liang, H.; Yang, F. CSN6 and Rab34 are involved in androgen receptor trafficking in mouse testicular sertoli cells. Cell. Physiol. Biochem.: Int. J. Experim. Cell. Physiol. Biochem. Pharmacol., 2018, 47, 2360-2368.
[35]
Liang, Y.; Lyon, R.; Pellman, J.; Mezzano, V.; Gu, Y.; Dalton, N.; Lee, M-H.; Iwakuma, T.; Nigam, V.; Peterson, K.; Sheikh, F. A newly identified interaction between desmoplakin and COP9 signalsome subunit 6 reveals a new mechanism underlying sudden death. Circulation, 2017, 136A18243
[36]
Wang, Z.; Xu, A.; Hou, X.; Chen, F.; Cao, W.; Yu, J.; Liao, M.; Tang, J. COP9 signalosome subunit 6 binds and inhibits avian leukosis virus integrase. Biochem. Biophys. Res. Commun., 2014, 453, 527-532.
[37]
Zhao, R.; Yeung, S.C.; Chen, J.; Iwakuma, T.; Su, C.H.; Chen, B.; Qu, C.; Zhang, F.; Chen, Y.T.; Lin, Y.L.; Lee, D.F.; Jin, F.; Zhu, R.; Shaikenov, T.; Sarbassov, D.; Sahin, A.; Wang, H.; Wang, H.; Lai, C.C.; Tsai, F.J.; Lozano, G.; Lee, M.H. Subunit 6 of the COP9 signalosome promotes tumorigenesis in mice through stabilization of MDM2 and is upregulated in human cancers. J. Clin. Invest., 2011, 121, 851-865.
[38]
Wee, S.; Geyer, R.K.; Toda, T.; Wolf, D.A. CSN facilitates Cullin-RING ubiquitin ligase function by counteracting autocatalytic adapter instability. Nat. Cell Biol., 2005, 7, 387-391.
[39]
Shin, J.; Phan, L.; Chen, J.; Lu, Z.; Lee, M.H. CSN6 positively regulates c-Jun in a MEKK1-dependent manner. Cell Cycle (Georgetown, Tex.), 2015, 14, 3079-3087.
[40]
Hou, J.; Deng, Q.; Zhou, J.; Zou, J.; Zhang, Y.; Tan, P.; Zhang, W.; Cui, H. CSN6 controls the proliferation and metastasis of glioblastoma by CHIP-mediated degradation of EGFR. Oncogene, 2017, 36, 1134-1144.
[41]
Zhu, Y.; Li, F.; Shi, W.; Zhai, C.; Wang, J.; Yan, X.; Wang, Q.; Zhang, Q.; Yang, L.; Gao, L.; Li, M. COP9 signalosome subunit 6 mediates PDGF -induced pulmonary arterial smooth muscle cells proliferation. Exp. Cell Res., 2018, 371, 379-388.
[42]
Chen, B.; Zhao, R.; Su, C.H.; Linan, M.; Tseng, C.; Phan, L.; Fang, L.; Yang, H.Y.; Yang, H.; Wang, W.; Xu, X.; Jiang, N.; Cai, S.; Jin, F.; Yeung, S.C.; Lee, M.H. CDK inhibitor p57 (Kip2) is negatively regulated by COP9 signalosome subunit 6. Cell Cycle (Georgetown, Tex.), 2012, 11, 4633-4641.
[43]
Choi, H.H.; Gully, C.; Su, C.H.; Velazquez-Torres, G.; Chou, P.C.; Tseng, C.; Zhao, R.; Phan, L.; Shaiken, T.; Chen, J.; Yeung, S.C.; Lee, M.H. COP9 signalosome subunit 6 stabilizes COP1, which functions as an E3 ubiquitin ligase for 14-3-3sigma. Oncogene, 2011, 30, 4791-4801.
[44]
Choi, H.H.; Guma, S.; Fang, L.; Phan, L.; Ivan, C.; Baggerly, K.; Sood, A.; Lee, M.H. Regulating the stability and localization of CDK inhibitor p27(Kip1) via CSN6-COP1 axis. Cell Cycle (Georgetown, Tex.), 2015, 14, 2265-2273.
[45]
Zhao, H.; Faltermeier, C.M.; Mendelsohn, L.; Porter, P.L.; Clurman, B.E.; Roberts, J.M. Mislocalization of p27 to the cytoplasm of breast cancer cells confers resistance to anti-HER2 targeted therapy. Oncotarget, 2014, 5, 12704-12714.
[46]
Choi, H.H.; Lee, M.H. CSN6-COP1 axis in cancer. Aging, 2015, 7, 461-462.
[47]
Choi, H.H.; Su, C.H.; Fang, L.; Zhang, J.; Yeung, S.C.; Lee, M.H. CSN6 deregulation impairs genome integrity in a COP1-dependent pathway. Oncotarget, 2015, 6, 11779-11793.
[48]
Yang, L.; Liu, Y.; Wang, M.; Qian, Y.; Dong, X.; Gu, H.; Wang, H.; Guo, S.; Hisamitsu, T. Quercetin-induced apoptosis of HT-29 colon cancer cells via inhibition of the Akt-CSN6-Myc signaling axis. Mol. Med. Rep., 2016, 14, 4559-4566.
[49]
Hetfeld, B.K.; Peth, A.; Sun, X.M.; Henklein, P.; Cohen, G.M.; Dubiel, W. The COP9 signalosome-mediated deneddylation is stimulated by caspases during apoptosis. Apoptosis: Int. J. Programmed Cell Death, 2008, 13, 187-195.
[50]
da Silva Correia, J.; Miranda, Y.; Leonard, N.; Ulevitch, R.J. The subunit CSN6 of the COP9 signalosome is cleaved during apoptosis. J. Biol. Chem., 2007, 282, 12557-12565.
[51]
Liu, S.; Chu, J.; Yucer, N.; Leng, M.; Wang, S.Y.; Chen, B.P.; Hittelman, W.N.; Wang, Y. RING finger and WD repeat domain 3 (RFWD3) associates with replication protein A (RPA) and facilitates RPA-mediated DNA damage response. J. Biol. Chem., 2011, 286, 22314-22322.
[52]
Wang, W.; Tang, M.; Zhang, L.; Xu, X.; Qi, X.; Yang, Y.; Jin, F.; Chen, B. Clinical implications of CSN6 protein expression and correlation with mutant-type P53 protein in breast cancer. Jap. J. Clin. Oncol., 2013, 43, 1170-1176.
[53]
Wen, D.; Liao, T.; Ma, B.; Qu, N.; Shi, R.L.; Lu, Z.W.; Wang, Y.L.; Wei, W.J.; Ji, Q.H. Downregulation of CSN6 attenuates papillary thyroid carcinoma progression by reducing Wnt/beta-catenin signaling and sensitizes cancer cells to FH535 therapy. Cancer Med., 2018, 7, 285-296.

Rights & Permissions Print Cite
© 2024 Bentham Science Publishers | Privacy Policy