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Frontiers of Medicine

ISSN 2095-0217

ISSN 2095-0225(Online)

CN 11-5983/R

邮发代号 80-967

2019 Impact Factor: 3.421

Frontiers of Medicine  2020, Vol. 14 Issue (3): 318-326   https://doi.org/10.1007/s11684-019-0708-6
  本期目录
Identification of an E3 ligase-encoding gene RFWD3 in non-small cell lung cancer
Yanfei Zhang1,2,3, Xinchun Zhao4, Yongchun Zhou5, Min Wang1,2, Guangbiao Zhou1,2,3()
1. State Key Laboratory of Membrane Biology, Institute of Zoology, Chinese Academy of Sciences, Beijing 100101, China
2. State Key Laboratory of Molecular Oncology, National Cancer Center/National Clinical Research Center for Cancer/Cancer Hospital, Chinese Academy of Medical Sciences and Peking Union Medical College, Beijing 100021, China
3. University of Chinese Academy of Sciences, Beijing 100049, China
4. School of Life Sciences, University of Science and Technology of China, Hefei 230026, China
5. Department of Thoracic Surgery, the Third Affiliated Hospital of Kunming Medical University, Kunming 650106, China
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Abstract

In order to unveil ubiquitin pathway genes (UPGs) that are essential for non-small cell lung cancer (NSCLC) cell proliferation, we recently conducted a siRNA screening experiment to knockdown the expression of 696 UPGs found in the human genome in A549 and H1975 NSCLC cells. We found that silencing of one of the candidates, RFWD3 that encodes an E3 ubiquitin ligase essential for the repair of DNA interstrand cross-links in response to DNA damage, led to dramatic inhibition of NSCLC cell proliferation with significant Z-scores. Knockdown of RFWD3 suppressed colony forming activity of NSCLC cells. We further evaluated the significance of RFWD3 in NSCLCs and found that this gene was more elevated in tumor samples than in paired normal lung tissues and was inversely associated with the clinical outcome of patients with NSCLC. Moreover, RFWD3 expression was significantly higher in smokers than in non-smokers. These results show for the first time that RFWD3 is required for NSCLC cell proliferation and may have an important role in lung carcinogenesis.

Key wordsRFWD3    NSCLC    prognosis    tobacco smoke
收稿日期: 2019-03-19      出版日期: 2020-06-08
Corresponding Author(s): Guangbiao Zhou   
 引用本文:   
. [J]. Frontiers of Medicine, 2020, 14(3): 318-326.
Yanfei Zhang, Xinchun Zhao, Yongchun Zhou, Min Wang, Guangbiao Zhou. Identification of an E3 ligase-encoding gene RFWD3 in non-small cell lung cancer. Front. Med., 2020, 14(3): 318-326.
 链接本文:  
https://academic.hep.com.cn/fmd/CN/10.1007/s11684-019-0708-6
https://academic.hep.com.cn/fmd/CN/Y2020/V14/I3/318
Fig.1  
Characteristics Cases, n RFWD3-high, n (%) P values*
Total number 22 14 (64)
Histology
Adenocarcinoma 17 11 (64.7) 0.519
Squamous cell carcinoma 5 4 (80)
Smoking
Smoker 10 9 (90) 0.019
Non-smoker 12 6 (50)
TNM stage
I–II 12 8 (66.7) 0.87
III–IV 10 7 (70)
Tab.1  
Fig.2  
Fig.3  
Fig.4  
Fig.5  
Fig.6  
1 D Wang, L Ma, B Wang, J Liu, W Wei. E3 ubiquitin ligases in cancer and implications for therapies. Cancer Metastasis Rev 2017; 36(4): 683–702
https://doi.org/10.1007/s10555-017-9703-z pmid: 29043469
2 K Kitagawa, M Kitagawa. The SCF-type E3 ubiquitin ligases as cancer targets. Curr Cancer Drug Targets 2016; 16(2): 119–129
https://doi.org/10.2174/1568009616666151112122231 pmid: 26560120
3 C Uchida, M Kitagawa. RING-, HECT-, and RBR-type E3 ubiquitin ligases: involvement in human cancer. Curr Cancer Drug Targets 2016; 16(2): 157–174
https://doi.org/10.2174/1568009616666151112122801 pmid: 26560116
4 N Zheng, N Shabek. Ubiquitin ligases: structure, function, and regulation. Annu Rev Biochem 2017; 86(1): 129–157
https://doi.org/10.1146/annurev-biochem-060815-014922 pmid: 28375744
5 J Liu, S Shaik, X Dai, Q Wu, X Zhou, Z Wang, W Wei. Targeting the ubiquitin pathway for cancer treatment. Biochim Biophys Acta 2015; 1855(1): 50–60
pmid: 25481052
6 M Gabrielsen, L Buetow, MA Nakasone, SF Ahmed, GJ Sibbet, BO Smith, W Zhang, SS Sidhu, DT Huang. A general strategy for discovery of inhibitors and activators of RING and U-box E3 ligases with ubiquitin variants. Mol Cell 2017; 68(2): 456–470.e10
https://doi.org/10.1016/j.molcel.2017.09.027 pmid: 29053960
7 JJ Mu, Y Wang, H Luo, M Leng, J Zhang, T Yang, D Besusso, SY Jung, J Qin. A proteomic analysis of ataxia telangiectasia-mutated (ATM)/ATM-Rad3-related (ATR) substrates identifies the ubiquitin-proteasome system as a regulator for DNA damage checkpoints. J Biol Chem 2007; 282(24): 17330–17334
https://doi.org/10.1074/jbc.C700079200 pmid: 17478428
8 X Fu, N Yucer, S Liu, M Li, P Yi, JJ Mu, T Yang, J Chu, SY Jung, BW O’Malley, W Gu, J Qin, Y Wang. RFWD3-Mdm2 ubiquitin ligase complex positively regulates p53 stability in response to DNA damage. Proc Natl Acad Sci USA 2010; 107(10): 4579–4584
https://doi.org/10.1073/pnas.0912094107 pmid: 20173098
9 Z Gong, J Chen. E3 ligase RFWD3 participates in replication checkpoint control. J Biol Chem 2011; 286(25): 22308–22313
https://doi.org/10.1074/jbc.M111.222869 pmid: 21504906
10 S Liu, J Chu, N Yucer, M Leng, SY Wang, BPC Chen, WN Hittelman, Y Wang. 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(25): 22314–22322
https://doi.org/10.1074/jbc.M111.222802 pmid: 21558276
11 K Knies, S Inano, MJ Ramírez, M Ishiai, J Surrallés, M Takata, D Schindler. Biallelic mutations in the ubiquitin ligase RFWD3 cause Fanconi anemia. J Clin Invest 2017; 127(8): 3013–3027
https://doi.org/10.1172/JCI92069 pmid: 28691929
12 JS Mitchell, N Li, N Weinhold, A Försti, M Ali, M van Duin, G Thorleifsson, DC Johnson, B Chen, BM Halvarsson, DF Gudbjartsson, R Kuiper, OW Stephens, U Bertsch, P Broderick, C Campo, H Einsele, WA Gregory, U Gullberg, M Henrion, J Hillengass, P Hoffmann, GH Jackson, E Johnsson, M Jöud, SY Kristinsson, S Lenhoff, O Lenive, UH Mellqvist, G Migliorini, H Nahi, S Nelander, J Nickel, MM Nöthen, T Rafnar, FM Ross, MI da Silva Filho, B Swaminathan, H Thomsen, I Turesson, A Vangsted, U Vogel, A Waage, BA Walker, AK Wihlborg, A Broyl, FE Davies, U Thorsteinsdottir, C Langer, M Hansson, M Kaiser, P Sonneveld, K Stefansson, GJ Morgan, H Goldschmidt, K Hemminki, B Nilsson, RS Houlston. Genome-wide association study identifies multiple susceptibility loci for multiple myeloma. Nat Commun 2016; 7: 12050
https://doi.org/10.1038/ncomms12050 pmid: 27363682
13 CC Chung, PA Kanetsky, Z Wang, MAT Hildebrandt, R Koster, RI Skotheim, CP Kratz, C Turnbull, VK Cortessis, AC Bakken, DT Bishop, MB Cook, RL Erickson, SD Fosså, KB Jacobs, LA Korde, SM Kraggerud, RA Lothe, JT Loud, N Rahman, EC Skinner, DC Thomas, X Wu, M Yeager, FR Schumacher, MH Greene, SM Schwartz, KA McGlynn, SJ Chanock, KL Nathanson. Meta-analysis identifies four new loci associated with testicular germ cell tumor. Nat Genet 2013; 45(6): 680–685
https://doi.org/10.1038/ng.2634 pmid: 23666239
14 DL Zhang, LW Qu, L Ma, YC Zhou, GZ Wang, XC Zhao, C Zhang, YF Zhang, M Wang, MY Zhang, H Yu, BB Sun, SH Gao, X Cheng, MZ Guo, YC Huang, GB Zhou. Genome-wide identification of transcription factors that are critical to non-small cell lung cancer. Cancer Lett 2018; 434: 132–143
https://doi.org/10.1016/j.canlet.2018.07.020 pmid: 30031117
15 N Malo, JA Hanley, S Cerquozzi, J Pelletier, R Nadon. Statistical practice in high-throughput screening data analysis. Nat Biotechnol 2006; 24(2): 167–175
https://doi.org/10.1038/nbt1186 pmid: 16465162
16 XC Zhao, GZ Wang, YC Zhou, J Liu, L Ma, C Zhang, DL Zhang, SH Gao, LW Qu, B Zhang, CL Wang, YC Huang, L Chen, GB Zhou. Genome-wide identification of CDC34 that stabilizes EGFR and promotes lung carcinogenesis. bioRxiv 2018
https://doi.org/10.1101/255844
17 DR Rhodes, S Kalyana-Sundaram, V Mahavisno, R Varambally, J Yu, BB Briggs, TR Barrette, MJ Anstet, C Kincead-Beal, P Kulkarni, S Varambally, D Ghosh, AM Chinnaiyan. Oncomine 3.0: genes, pathways, and networks in a collection of 18,000 cancer gene expression profiles. Neoplasia 2007; 9(2): 166–180
https://doi.org/10.1593/neo.07112 pmid: 17356713
18 J Hou, J Aerts, B den Hamer, W van Ijcken, M den Bakker, P Riegman, C van der Leest, P van der Spek, JA Foekens, HC Hoogsteden, F Grosveld, S Philipsen. Gene expression-based classification of non-small cell lung carcinomas and survival prediction. PLoS One 2010; 5(4): e10312
https://doi.org/10.1371/journal.pone.0010312 pmid: 20421987
19 SA Selamat, BS Chung, L Girard, W Zhang, Y Zhang, M Campan, KD Siegmund, MN Koss, JA Hagen, WL Lam, S Lam, AF Gazdar, IA Laird-Offringa. Genome-scale analysis of DNA methylation in lung adenocarcinoma and integration with mRNA expression. Genome Res 2012; 22(7): 1197–1211
https://doi.org/10.1101/gr.132662.111 pmid: 22613842
20 MT Landi, T Dracheva, M Rotunno, JD Figueroa, H Liu, A Dasgupta, FE Mann, J Fukuoka, M Hames, AW Bergen, SE Murphy, P Yang, AC Pesatori, D Consonni, PA Bertazzi, S Wacholder, JH Shih, NE Caporaso, J Jen. Gene expression signature of cigarette smoking and its role in lung adenocarcinoma development and survival. PLoS One 2008; 3(2): e1651
https://doi.org/10.1371/journal.pone.0001651 pmid: 18297132
21 H Okayama, T Kohno, Y Ishii, Y Shimada, K Shiraishi, R Iwakawa, K Furuta, K Tsuta, T Shibata, S Yamamoto, S Watanabe, H Sakamoto, K Kumamoto, S Takenoshita, N Gotoh, H Mizuno, A Sarai, S Kawano, R Yamaguchi, S Miyano, J Yokota. Identification of genes upregulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas. Cancer Res 2012; 72(1): 100–111
https://doi.org/10.1158/0008-5472.CAN-11-1403 pmid: 22080568
22 S Wachi, K Yoneda, R Wu. Interactome-transcriptome analysis reveals the high centrality of genes differentially expressed in lung cancer tissues. Bioinformatics 2005; 21(23): 4205–4208
https://doi.org/10.1093/bioinformatics/bti688 pmid: 16188928
23 RS Stearman, L Dwyer-Nield, L Zerbe, SA Blaine, Z Chan, PA Bunn Jr, GL Johnson, FR Hirsch, DT Merrick, WA Franklin, AE Baron, RL Keith, RA Nemenoff, AM Malkinson, MW Geraci. Analysis of orthologous gene expression between human pulmonary adenocarcinoma and a carcinogen-induced murine model. Am J Pathol 2005; 167(6): 1763–1775
https://doi.org/10.1016/S0002-9440(10)61257-6 pmid: 16314486
24 TP Lu, MH Tsai, JM Lee, CP Hsu, PC Chen, CW Lin, JY Shih, PC Yang, CK Hsiao, LC Lai, EY Chuang. Identification of a novel biomarker, SEMA5A, for non-small cell lung carcinoma in nonsmoking women. Cancer Epidemiol Biomarkers Prev 2010; 19(10): 2590–2597
https://doi.org/10.1158/1055-9965.EPI-10-0332 pmid: 20802022
25 L Ma, Y Huang, W Zhu, S Zhou, J Zhou, F Zeng, X Liu, Y Zhang, J Yu. An integrated analysis of miRNA and mRNA expressions in non-small cell lung cancers. PLoS One 2011; 6(10): e26502
https://doi.org/10.1371/journal.pone.0026502 pmid: 22046296
26 H Okayama, T Kohno, Y Ishii, Y Shimada, K Shiraishi, R Iwakawa, K Furuta, K Tsuta, T Shibata, S Yamamoto, S Watanabe, H Sakamoto, K Kumamoto, S Takenoshita, N Gotoh, H Mizuno, A Sarai, S Kawano, R Yamaguchi, S Miyano, J Yokota. Identification of genes upregulated in ALK-positive and EGFR/KRAS/ALK-negative lung adenocarcinomas. Cancer Res 2012; 72(1): 100–111
https://doi.org/10.1158/0008-5472.CAN-11-1403 pmid: 22080568
27 MC Tai, T Kajino, M Nakatochi, C Arima, Y Shimada, M Suzuki, H Miyoshi, Y Yatabe, K Yanagisawa, T Takahashi. miR-342-3p regulates MYC transcriptional activity via direct repression of E2F1 in human lung cancer. Carcinogenesis 2015; 36(12): 1464–1473
https://doi.org/10.1093/carcin/bgv152 pmid: 26483346
28 B Győrffy, P Surowiak, J Budczies, A Lánczky. Online survival analysis software to assess the prognostic value of biomarkers using transcriptomic data in non-small-cell lung cancer. PLoS One 2013; 8(12): e82241
https://doi.org/10.1371/journal.pone.0082241 pmid: 24367507
29 ES Lee, DS Son, SH Kim, J Lee, J Jo, J Han, H Kim, HJ Lee, HY Choi, Y Jung, M Park, YS Lim, K Kim, Y Shim, BC Kim, K Lee, N Huh, C Ko, K Park, JW Lee, YS Choi, J Kim. Prediction of recurrence-free survival in postoperative non-small cell lung cancer patients by using an integrated model of clinical information and gene expression. Clin Cancer Res 2008; 14(22): 7397–7404
https://doi.org/10.1158/1078-0432.CCR-07-4937 pmid: 19010856
30 J Staaf, G Jönsson, M Jönsson, A Karlsson, S Isaksson, A Salomonsson, HM Pettersson, M Soller, SB Ewers, L Johansson, P Jönsson, M Planck. Relation between smoking history and gene expression profiles in lung adenocarcinomas. BMC Med Genomics 2012; 5(1): 22
https://doi.org/10.1186/1755-8794-5-22 pmid: 22676229
31 T Ravid, M Hochstrasser. Diversity of degradation signals in the ubiquitin-proteasome system. Nat Rev Mol Cell Biol 2008; 9(9): 679–689
https://doi.org/10.1038/nrm2468 pmid: 18698327
32 BC Snoek, LH de Wilt, G Jansen, GJ Peters. Role of E3 ubiquitin ligases in lung cancer. World J Clin Oncol 2013; 4(3): 58–69
https://doi.org/10.5306/wjco.v4.i3.58 pmid: 23936758
33 K Kok, R Hofstra, A Pilz, A van den Berg, P Terpstra, CH Buys, B Carritt. A gene in the chromosomal region 3p21 with greatly reduced expression in lung cancer is similar to the gene for ubiquitin-activating enzyme. Proc Natl Acad Sci USA 1993; 90(13): 6071–6075
https://doi.org/10.1073/pnas.90.13.6071 pmid: 8327486
34 P Pallante, U Malapelle, MT Berlingieri, C Bellevicine, R Sepe, A Federico, D Rocco, M Galgani, L Chiariotti, M Sanchez-Cespedes, A Fusco, G Troncone. UbcH10 overexpression in human lung carcinomas and its correlation with EGFR and p53 mutational status. Eur J Cancer 2013; 49(5): 1117–1126
https://doi.org/10.1016/j.ejca.2012.09.033 pmid: 23102841
35 H Kadara, L Lacroix, C Behrens, L Solis, X Gu, JJ Lee, E Tahara, D Lotan, WK Hong, II Wistuba, R Lotan. Identification of gene signatures and molecular markers for human lung cancer prognosis using an in vitro lung carcinogenesis system. Cancer Prev Res (Phila) 2009; 2(8): 702–711
https://doi.org/10.1158/1940-6207.CAPR-09-0084 pmid: 19638491
36 H Sasaki, S Moriyama, Y Nakashima, H Yukiue, I Fukai, Y Fujii. Decreased Hrad6B expression in lung cancer. Acta Oncol 2004; 43(6): 585–589
https://doi.org/10.1080/02841860410014920 pmid: 15370617
37 YHC Tan, S Krishnaswamy, S Nandi, R Kanteti, S Vora, K Onel, R Hasina, FY Lo, E El-Hashani, G Cervantes, M Robinson, HS Hsu, SC Kales, S Lipkowitz, T Karrison, M Sattler, EE Vokes, YC Wang, R Salgia. CBL is frequently altered in lung cancers: its relationship to mutations in MET and EGFR tyrosine kinases. PLoS One 2010; 5(1): e8972
https://doi.org/10.1371/journal.pone.0008972 pmid: 20126411
38 AU Ahmed, RL Schmidt, CH Park, NR Reed, SE Hesse, CF Thomas, JR Molina, C Deschamps, P Yang, MC Aubry, AH Tang. Effect of disrupting seven-in-absentia homolog 2 function on lung cancer cell growth. J Natl Cancer Inst 2008; 100(22): 1606–1629
https://doi.org/10.1093/jnci/djn365 pmid: 19001609
39 JJ Sacco, TY Yau, S Darling, V Patel, H Liu, S Urbé, MJ Clague, JM Coulson. The deubiquitylase Ataxin-3 restricts PTEN transcription in lung cancer cells. Oncogene 2014; 33(33): 4265–4272
https://doi.org/10.1038/onc.2013.512 pmid: 24292675
40 S Byun, SY Lee, J Lee, CH Jeong, L Farrand, S Lim, K Reddy, JY Kim, MH Lee, HJ Lee, AM Bode, K Won Lee, Z Dong. USP8 is a novel target for overcoming gefitinib resistance in lung cancer. Clin Cancer Res 2013; 19(14): 3894–3904
https://doi.org/10.1158/1078-0432.CCR-12-3696 pmid: 23748694
41 C McFarlane, S McFarlane, I Paul, K Arthur, M Scheaff, K Kerr, M Stevenson, DA Fennell, JA Johnston. The deubiquitinating enzyme USP17 is associated with non-small cell lung cancer (NSCLC) recurrence and metastasis. Oncotarget 2013; 4(10): 1836–1843
https://doi.org/10.18632/oncotarget.1282 pmid: 24123619
42 J Pan, Q Deng, C Jiang, X Wang, T Niu, H Li, T Chen, J Jin, W Pan, X Cai, X Yang, M Lu, J Xiao, P Wang. USP37 directly deubiquitinates and stabilizes c-Myc in lung cancer. Oncogene 2015; 34(30): 3957–3967
https://doi.org/10.1038/onc.2014.327 pmid: 25284584
43 YQ Liu, XL Wang, X Cheng, YZ Lu, GZ Wang, XC Li, J Zhang, ZS Wen, ZL Huang, QL Gao, LN Yang, YX Cheng, SC Tao, J Liu, GB Zhou. Skp1 in lung cancer: clinical significance and therapeutic efficacy of its small molecule inhibitors. Oncotarget 2015; 6(33): 34953–34967
https://doi.org/10.18632/oncotarget.5547 pmid: 26474281
44 YC Lin, Y Wang, R Hsu, S Giri, S Wopat, MK Arif, A Chakraborty, KV Prasanth, SG Prasanth. PCNA-mediated stabilization of E3 ligase RFWD3 at the replication fork is essential for DNA replication. Proc Natl Acad Sci USA 2018; 115(52): 13282–13287
https://doi.org/10.1073/pnas.1814521115 pmid: 30530694
45 S Inano, K Sato, Y Katsuki, W Kobayashi, H Tanaka, K Nakajima, S Nakada, H Miyoshi, K Knies, A Takaori-Kondo, D Schindler, M Ishiai, H Kurumizaka, M Takata. RFWD3-mediated ubiquitination promotes timely removal of both RPA and RAD51 from DNA damage sites to facilitate homologous recombination. Mol Cell 2017; 66(5): 622–634.e8
https://doi.org/10.1016/j.molcel.2017.04.022 pmid: 28575658
46 L Feeney, IM Muñoz, C Lachaud, R Toth, PL Appleton, D Schindler, J Rouse. RPA-mediated recruitment of the E3 ligase RFWD3 is vital for interstrand crosslink repair and human health. Mol Cell 2017; 66(5): 610–621.e4
https://doi.org/10.1016/j.molcel.2017.04.021 pmid: 28575657
47 World Health Organization. Ambient (outdoor) air quality and health. . 2018. Accessed November 22, 2018
48 World Health Organization. Household air pollution and health. . 2018. Accessed December 24, 2018
49 World Health Organization. Tobacco fact sheet. . 2019. Accessed December 24, 2018
50 LB Alexandrov, YS Ju, K Haase, P Van Loo, I Martincorena, S Nik-Zainal, Y Totoki, A Fujimoto, H Nakagawa, T Shibata, PJ Campbell, P Vineis, DH Phillips, MR Stratton. Mutational signatures associated with tobacco smoking in human cancer. Science 2016; 354(6312): 618–622
https://doi.org/10.1126/science.aag0299 pmid: 27811275
51 R Govindan, L Ding, M Griffith, J Subramanian, ND Dees, KL Kanchi, CA Maher, R Fulton, L Fulton, J Wallis, K Chen, J Walker, S McDonald, R Bose, D Ornitz, D Xiong, M You, DJ Dooling, M Watson, ER Mardis, RK Wilson. Genomic landscape of non-small cell lung cancer in smokers and never-smokers. Cell 2012; 150(6): 1121–1134
https://doi.org/10.1016/j.cell.2012.08.024 pmid: 22980976
52 C Gibelin, S Couraud. Somatic alterations in lung cancer: do environmental factors matter? Lung Cancer 2016; 100: 45–52
https://doi.org/10.1016/j.lungcan.2016.07.015 pmid: 27597280
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