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Current Pharmaceutical Biotechnology

Editor-in-Chief

ISSN (Print): 1389-2010
ISSN (Online): 1873-4316

Research Article

Lysine-specific Demethylase 6A Upregulates Cadherin-1 and Accelerates Gastric Cancer Growth

Author(s): Deguan Li, Shangxin Zhang, Qiang Yan and Yongxiang Li*

Volume 24, Issue 14, 2023

Published on: 27 April, 2023

Page: [1827 - 1835] Pages: 9

DOI: 10.2174/1389201024666230320100504

Price: $65

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Abstract

Background: Gastric cancer (GC) ranks fifth among all common malignancies globally. Genetic research has revealed several genes that are frequently dis-regulated in GC, such as lysine-specific demethylase 6A (KDM6A) and cadherin-1 (CDH1).

Objective: This study aimed to examine the expression profile and role of KDM6A in GC, as well as the molecular pathway involved.

Methods: The expression profile and overall survival data of KDM6A were retrieved from the TCGA database. Expression levels of KDM6A were also measured in GC patient samples and compared with those of healthy controls. Furthermore, stable silencing of KDM6A was introduced into the GC cell line NCI-N87, followed by assessments of cell proliferation, migration and invasion, in the xenograft mouse model. The metastatic status of mice injected with NCI-N87 cells was also analyzed.

Results: In patients diagnosed with GC, KDM6A was upregulated. Silencing KDM6A reduced the proliferation, migration and invasion of cells, as well as the growth of xenograft tumors. KDM6A knockdown also inhibited metastatic behaviors of injected NCI-N87 cells, as well as elevated CDH1 expression, leading to reversed epithelial-mesenchymal transition.

Conclusion: KDM6A serves as an oncogene in GC and exerts its pro-tumor functions by repressing the expression of CDH1.

Keywords: KDM6A, CDH1, gastric cancer, metastasis, NCI-N87 cells, oncogene.

Graphical Abstract
[1]
Gong, D.; Hai, J.; Ma, J.; Wang, C-X.; Zhang, X-D.; Xiang, Y-N.; Tan, T.; Liu, Y-N.; Zhang, W. ML-SA1, a TRPML1 agonist, induces gastric secretion and gastrointestinal tract inflammation in vivo. STEMedicine, 2020, 1(1), e3.
[http://dx.doi.org/10.37175/stemedicine.v1i1.3]
[2]
Sung, H.; Ferlay, J.; Siegel, R.L.; Laversanne, M.; Soerjomataram, I.; Jemal, A.; Bray, F. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J. Clin., 2021, 71(3), 209-249.
[http://dx.doi.org/10.3322/caac.21660] [PMID: 33538338]
[3]
Orditura, M.; Galizia, G.; Sforza, V.; Gambardella, V.; Fabozzi, A.; Laterza, M.M.; Andreozzi, F.; Ventriglia, J.; Savastano, B.; Mabilia, A.; Lieto, E.; Ciardiello, F.; De Vita, F. Treatment of gastric cancer. World J. Gastroenterol., 2014, 20(7), 1635-1649.
[http://dx.doi.org/10.3748/wjg.v20.i7.1635] [PMID: 24587643]
[4]
Bang, Y.J.; Van Cutsem, E.; Feyereislova, A.; Chung, H.C.; Shen, L.; Sawaki, A.; Lordick, F.; Ohtsu, A.; Omuro, Y.; Satoh, T.; Aprile, G.; Kulikov, E.; Hill, J.; Lehle, M.; Rüschoff, J.; Kang, Y.K. Trastuzumab in combination with chemotherapy versus chemotherapy alone for treatment of HER2-positive advanced gastric or gastro-oesophageal junction cancer (ToGA): A phase 3, open-label, randomised controlled trial. Lancet, 2010, 376(9742), 687-697.
[http://dx.doi.org/10.1016/S0140-6736(10)61121-X] [PMID: 20728210]
[5]
Laurén, P. The two histological main types of gastric carcinoma: Diffuse and so-called intestinal-type carcinoma. an attempt at a histo-clinical classification. Acta Pathol. Microbiol. Scand., 1965, 64(1), 31-49.
[http://dx.doi.org/10.1111/apm.1965.64.1.31] [PMID: 14320675]
[6]
Cisło, M.; Filip, A.A.; Arnold Offerhaus, G.J.; Ciseł, B.; Rawicz-Pruszyński, K.; Skierucha, M.; Polkowski, W.P. Distinct molecular subtypes of gastric cancer: From Laurén to molecular pathology. Oncotarget, 2018, 9(27), 19427-19442.
[http://dx.doi.org/10.18632/oncotarget.24827] [PMID: 29721214]
[7]
Kakiuchi, M.; Nishizawa, T.; Ueda, H.; Gotoh, K.; Tanaka, A.; Hayashi, A.; Yamamoto, S.; Tatsuno, K.; Katoh, H.; Watanabe, Y.; Ichimura, T.; Ushiku, T.; Funahashi, S.; Tateishi, K.; Wada, I.; Shimizu, N.; Nomura, S.; Koike, K.; Seto, Y.; Fukayama, M.; Aburatani, H.; Ishikawa, S. Recurrent gain-of-function mutations of RHOA in diffuse-type gastric carcinoma. Nat. Genet., 2014, 46(6), 583-587.
[http://dx.doi.org/10.1038/ng.2984] [PMID: 24816255]
[8]
Cho, J.; Ahn, S.; Son, D.S.; Kim, N.K.D.; Lee, K.W.; Kim, S.; Lee, J.; Park, S.H.; Park, J.O.; Kang, W.K.; An, J.Y.; Choi, M.G.; Lee, J.H.; Sohn, T.S.; Bae, J.M.; Kim, S.; Kim, K.M. Bridging genomics and phenomics of gastric carcinoma. Int. J. Cancer, 2019, 145(9), 2407-2417.
[http://dx.doi.org/10.1002/ijc.32228] [PMID: 30801717]
[9]
Cai, H.; Jing, C.; Chang, X.; Ding, D.; Han, T.; Yang, J.; Lu, Z.; Hu, X.; Liu, Z.; Wang, J.; Shang, L.; Wu, S.; Meng, P.; Lin, L.; Zhao, J.; Nie, M.; Yin, K. Mutational landscape of gastric cancer and clinical application of genomic profiling based on target next-generation sequencing. J. Transl. Med., 2019, 17(1), 189.
[http://dx.doi.org/10.1186/s12967-019-1941-0] [PMID: 31164161]
[10]
Cancer Genome Atlas Research Network. Comprehensive molecular characterization of gastric adenocarcinoma. Nature, 2014, 513(7517), 202-209.
[http://dx.doi.org/10.1038/nature13480] [PMID: 25079317]
[11]
Fitzgerald, R.C.; Hardwick, R.; Huntsman, D.; Carneiro, F.; Guilford, P.; Blair, V.; Chung, D.C.; Norton, J.; Ragunath, K.; Van Krieken, J.H.; Dwerryhouse, S.; Caldas, C. Hereditary diffuse gastric cancer: Updated consensus guidelines for clinical management and directions for future research. J. Med. Genet., 2010, 47(7), 436-444.
[http://dx.doi.org/10.1136/jmg.2009.074237] [PMID: 20591882]
[12]
Becker, K.F.; Atkinson, M.J.; Reich, U.; Becker, I.; Nekarda, H.; Siewert, J.R.; Höfler, H. E-cadherin gene mutations provide clues to diffuse type gastric carcinomas. Cancer Res., 1994, 54(14), 3845-3852.
[PMID: 8033105]
[13]
Caldas, C.; Carneiro, F.; Lynch, H.T.; Yokota, J.; Wiesner, G.L.; Powell, S.M.; Lewis, F.R.; Huntsman, D.G.; Pharoah, P.D.; Jankowski, J.A.; MacLeod, P.; Vogelsang, H.; Keller, G.; Park, K.G.; Richards, F.M.; Maher, E.R.; Gayther, S.A.; Oliveira, C.; Grehan, N.; Wight, D.; Seruca, R.; Roviello, F.; Ponder, B.A.; Jackson, C.E. Familial gastric cancer: Overview and guidelines for management. J. Med. Genet., 1999, 36(12), 873-880.
[PMID: 10593993]
[14]
Machado, J.C.; Oliveira, C.; Carvalho, R.; Soares, P.; Berx, G.; Caldas, C.; Seruca, R.; Carneiro, F.; Sobrinho-Simöes, M. E-cadherin gene (CDH1) promoter methylation as the second hit in sporadic diffuse gastric carcinoma. Oncogene, 2001, 20(12), 1525-1528.
[http://dx.doi.org/10.1038/sj.onc.1204234] [PMID: 11313896]
[15]
Corso, G.; Carvalho, J.; Marrelli, D.; Vindigni, C.; Carvalho, B.; Seruca, R.; Roviello, F.; Oliveira, C. Somatic mutations and deletions of the E-cadherin gene predict poor survival of patients with gastric cancer. J. Clin. Oncol., 2013, 31(7), 868-875.
[http://dx.doi.org/10.1200/JCO.2012.44.4612] [PMID: 23341533]
[16]
Wang, Y.; Chen, Z. Mutation detection and molecular targeted tumor therapies. STEMedicine, 2020, 1(1), e11.
[http://dx.doi.org/10.37175/stemedicine.v1i1.11]
[17]
van Roy, F.; Berx, G. The cell-cell adhesion molecule E-cadherin. Cell. Mol. Life Sci., 2008, 65(23), 3756-3788.
[http://dx.doi.org/10.1007/s00018-008-8281-1] [PMID: 18726070]
[18]
Bracke, M.E.; Roy, F.M.V.; Mareel, M.M. The E-cadherin/catenin complex in invasion and metastasis. Curr. Top. Microbiol. Immunol., 1996, 213(Pt 1), 123-161.
[http://dx.doi.org/10.1007/978-3-642-61107-0_9] [PMID: 8814984]
[19]
Carneiro, F.; Huntsman, D.G.; Smyrk, T.C.; Owen, D.A.; Seruca, R.; Pharoah, P.; Caldas, C.; Sobrinho-Simões, M. Model of the early development of diffuse gastric cancer in E-cadherin mutation carriers and its implications for patient screening. J. Pathol., 2004, 203(2), 681-687.
[http://dx.doi.org/10.1002/path.1564] [PMID: 15141383]
[20]
Barber, M.; Murrell, A.; Ito, Y.; Maia, A-T.; Hyland, S.; Oliveira, C.; Save, V.; Carneiro, F.; Paterson, A.L.; Grehan, N.; Dwerryhouse, S.; Lao-Sirieix, P.; Caldas, C.; Fitzgerald, R.C. Mechanisms and sequelae of E-cadherin silencing in hereditary diffuse gastric cancer. J. Pathol., 2008, 216(3), 295-306.
[http://dx.doi.org/10.1002/path.2426] [PMID: 18788075]
[21]
Klezovitch, O.; Vasioukhin, V. Cadherin signaling: Keeping cells in touch. F1000Res, 2015, 4(F1000 Faculty Rev), 550.
[http://dx.doi.org/10.12688/f1000research.6445.1]
[22]
Yu, W.; Yang, L.; Li, T.; Zhang, Y. Cadherin signaling in cancer: Its functions and role as a therapeutic target. Front. Oncol., 2019, 9, 989.
[http://dx.doi.org/10.3389/fonc.2019.00989] [PMID: 31637214]
[23]
Tran, N.; Broun, A.; Ge, K. Lysine demethylase KDM6A in differentiation, development, and cancer. Mol. Cell. Biol., 2020, 40(20), e00341-20.
[http://dx.doi.org/10.1128/MCB.00341-20] [PMID: 32817139]
[24]
Lee, S.W.; Park, D.Y.; Kim, M.Y.; Kang, C. Synergistic triad epistasis of epigenetic H3K27me modifier genes, EZH2, KDM6A, and KDM6B, in gastric cancer susceptibility. Gastric Cancer, 2019, 22(3), 640-644.
[http://dx.doi.org/10.1007/s10120-018-0888-9] [PMID: 30374835]
[25]
Tiscornia, G.; Singer, O.; Verma, I.M. Production and purification of lentiviral vectors. Nat. Protoc., 2006, 1(1), 241-245.
[http://dx.doi.org/10.1038/nprot.2006.37] [PMID: 17406239]
[26]
Chandrashekar, D.S.; Bashel, B.; Balasubramanya, S.A.H.; Creighton, C.J.; Ponce-Rodriguez, I.; Chakravarthi, B.V.S.K.; Varambally, S. UALCAN: A portal for facilitating tumor subgroup gene expression and survival analyses. Neoplasia, 2017, 19(8), 649-658.
[http://dx.doi.org/10.1016/j.neo.2017.05.002] [PMID: 28732212]
[27]
Szász, A.M.; Lánczky, A.; Nagy, Á.; Förster, S.; Hark, K.; Green, J.E.; Boussioutas, A.; Busuttil, R.; Szabó, A.; Győrffy, B. Cross-validation of survival associated biomarkers in gastric cancer using transcriptomic data of 1,065 patients. Oncotarget, 2016, 7(31), 49322-49333.
[http://dx.doi.org/10.18632/oncotarget.10337] [PMID: 27384994]
[28]
Liu, X.; Chu, K.M. E-cadherin and gastric cancer: Cause, consequence, and applications. Bio. Med. Res. Int., 2014, 2014, 1-9.
[http://dx.doi.org/10.1155/2014/637308] [PMID: 25184143]
[29]
Agger, K.; Cloos, P.A.C.; Christensen, J.; Pasini, D.; Rose, S.; Rappsilber, J.; Issaeva, I.; Canaani, E.; Salcini, A.E.; Helin, K. UTX and JMJD3 are histone H3K27 demethylases involved in HOX gene regulation and development. Nature, 2007, 449(7163), 731-734.
[http://dx.doi.org/10.1038/nature06145] [PMID: 17713478]
[30]
Hong, S.; Cho, Y.W.; Yu, L.R.; Yu, H.; Veenstra, T.D.; Ge, K. Identification of JmjC domain-containing UTX and JMJD3 as histone H3 lysine 27 demethylases. Proc. Natl. Acad. Sci., 2007, 104(47), 18439-18444.
[http://dx.doi.org/10.1073/pnas.0707292104] [PMID: 18003914]
[31]
Lan, F.; Bayliss, P.E.; Rinn, J.L.; Whetstine, J.R.; Wang, J.K.; Chen, S.; Iwase, S.; Alpatov, R.; Issaeva, I.; Canaani, E.; Roberts, T.M.; Chang, H.Y.; Shi, Y. A histone H3 lysine 27 demethylase regulates animal posterior development. Nature, 2007, 449(7163), 689-694.
[http://dx.doi.org/10.1038/nature06192] [PMID: 17851529]
[32]
Lee, M.G.; Villa, R.; Trojer, P.; Norman, J.; Yan, K.P.; Reinberg, D.; Di Croce, L.; Shiekhattar, R. Demethylation of H3K27 regulates polycomb recruitment and H2A ubiquitination. Science, 2007, 318(5849), 447-450.
[http://dx.doi.org/10.1126/science.1149042] [PMID: 17761849]
[33]
van Haaften, G.; Dalgliesh, G.L.; Davies, H.; Chen, L.; Bignell, G.; Greenman, C.; Edkins, S.; Hardy, C.; O’Meara, S.; Teague, J.; Butler, A.; Hinton, J.; Latimer, C.; Andrews, J.; Barthorpe, S.; Beare, D.; Buck, G.; Campbell, P.J.; Cole, J.; Forbes, S.; Jia, M.; Jones, D.; Kok, C.Y.; Leroy, C.; Lin, M.L.; McBride, D.J.; Maddison, M.; Maquire, S.; McLay, K.; Menzies, A.; Mironenko, T.; Mulderrig, L.; Mudie, L.; Pleasance, E.; Shepherd, R.; Smith, R.; Stebbings, L.; Stephens, P.; Tang, G.; Tarpey, P.S.; Turner, R.; Turrell, K.; Varian, J.; West, S.; Widaa, S.; Wray, P.; Collins, V.P.; Ichimura, K.; Law, S.; Wong, J.; Yuen, S.T.; Leung, S.Y.; Tonon, G.; DePinho, R.A.; Tai, Y.T.; Anderson, K.C.; Kahnoski, R.J.; Massie, A.; Khoo, S.K.; Teh, B.T.; Stratton, M.R.; Futreal, P.A. Somatic mutations of the histone H3K27 demethylase gene UTX in human cancer. Nat. Genet., 2009, 41(5), 521-523.
[http://dx.doi.org/10.1038/ng.349] [PMID: 19330029]
[34]
Lawrence, M.S.; Stojanov, P.; Mermel, C.H.; Robinson, J.T.; Garraway, L.A.; Golub, T.R.; Meyerson, M.; Gabriel, S.B.; Lander, E.S.; Getz, G. Discovery and saturation analysis of cancer genes across 21 tumour types. Nature, 2014, 505(7484), 495-501.
[http://dx.doi.org/10.1038/nature12912] [PMID: 24390350]
[35]
Ler, L.D.; Ghosh, S.; Chai, X.; Thike, A.A.; Heng, H.L.; Siew, E.Y.; Dey, S.; Koh, L.K.; Lim, J.Q.; Lim, W.K.; Myint, S.S.; Loh, J.L.; Ong, P.; Sam, X.X.; Huang, D.; Lim, T.; Tan, P.H.; Nagarajan, S.; Cheng, C.W.S.; Ho, H.; Ng, L.G.; Yuen, J.; Lin, P.H.; Chuang, C.K.; Chang, Y.H.; Weng, W.H.; Rozen, S.G.; Tan, P.; Creasy, C.L.; Pang, S.T.; McCabe, M.T.; Poon, S.L.; Teh, B.T. Loss of tumor suppressor KDM6A amplifies PRC2-regulated transcriptional repression in bladder cancer and can be targeted through inhibition of EZH2. Sci. Transl. Med., 2017, 9(378), eaai8312.
[http://dx.doi.org/10.1126/scitranslmed.aai8312] [PMID: 28228601]
[36]
Kaneko, S.; Li, X. X chromosome protects against bladder cancer in females via a KDM6A -dependent epigenetic mechanism. Sci. Adv., 2018, 4(6), eaar5598.
[http://dx.doi.org/10.1126/sciadv.aar5598] [PMID: 29928692]
[37]
Kobatake, K.; Ikeda, K.; Nakata, Y.; Yamasaki, N.; Ueda, T.; Kanai, A.; Sentani, K.; Sera, Y.; Hayashi, T.; Koizumi, M.; Miyakawa, Y.; Inaba, T.; Sotomaru, Y.; Kaminuma, O.; Ichinohe, T.; Honda, Z.; Yasui, W.; Horie, S.; Black, P.C.; Matsubara, A.; Honda, H. Kdm6a deficiency activates inflammatory pathways, promotes M2 macrophage polarization, and causes bladder cancer in cooperation with p53 dysfunction. Clin. Cancer Res., 2020, 26(8), 2065-2079.
[http://dx.doi.org/10.1158/1078-0432.CCR-19-2230] [PMID: 32047002]
[38]
Wu, Q.; Tian, Y.; Zhang, J.; Tong, X.; Huang, H.; Li, S.; Zhao, H.; Tang, Y.; Yuan, C.; Wang, K.; Fang, Z.; Gao, L.; Hu, X.; Li, F.; Qin, Z.; Yao, S.; Chen, T.; Chen, H.; Zhang, G.; Liu, W.; Sun, Y.; Chen, L.; Wong, K.K.; Ge, K.; Chen, L.; Ji, H. In vivo CRISPR screening unveils histone demethylase UTX as an important epigenetic regulator in lung tumorigenesis. Proc. Natl. Acad. Sci., 2018, 115(17), E3978-E3986.
[http://dx.doi.org/10.1073/pnas.1716589115] [PMID: 29632194]
[39]
Watanabe, S.; Shimada, S.; Akiyama, Y.; Ishikawa, Y.; Ogura, T.; Ogawa, K.; Ono, H.; Mitsunori, Y.; Ban, D.; Kudo, A.; Yamaoka, S.; Tanabe, M.; Tanaka, S. Loss of KDM6A characterizes a poor prognostic subtype of human pancreatic cancer and potentiates HDAC inhibitor lethality. Int. J. Cancer, 2019, 145(1), 192-205.
[http://dx.doi.org/10.1002/ijc.32072] [PMID: 30556125]
[40]
Kalisz, M.; Bernardo, E.; Beucher, A.; Maestro, M.A.; del Pozo, N.; Millán, I.; Haeberle, L.; Schlensog, M.; Safi, S.A.; Knoefel, W.T.; Grau, V.; de Vas, M.; Shpargel, K.B.; Vaquero, E.; Magnuson, T.; Ortega, S.; Esposito, I.; Real, F.X.; Ferrer, J. HNF1A recruits KDM6A to activate differentiated acinar cell programs that suppress pancreatic cancer. EMBO J., 2020, 39(9), e102808.
[http://dx.doi.org/10.15252/embj.2019102808] [PMID: 32154941]
[41]
Andricovich, J.; Perkail, S.; Kai, Y.; Casasanta, N.; Peng, W.; Tzatsos, A. Loss of KDM6A activates super-enhancers to induce gender-specific squamous-like pancreatic cancer and confers sensitivity to BET inhibitors. Cancer Cell, 2018, 33(3), 512-526.e8.
[http://dx.doi.org/10.1016/j.ccell.2018.02.003] [PMID: 29533787]

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