Clinicopathological significance of G9A expression in colorectal carcinoma

Qin,Jian; Zeng,Zhi; Luo,Tao; Li,Qingyun; Hao,Yarong; Chen,Lang

doi:10.3892/ol.2018.8446

Clinicopathological significance of G9A expression in colorectal carcinoma

Authors:
- Jian Qin
- Zhi Zeng
- Tao Luo
- Qingyun Li
- Yarong Hao
- Lang Chen
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Affiliations: Central Laboratory, Wuhan University, Renmin Hospital, Wuhan, Hubei 430060, P.R. China, Department of Pathology, Wuhan University, Renmin Hospital, Wuhan, Hubei 430060, P.R. China, Department of Anesthesiology, Peking University Shenzhen Hospital, Shenzhen, Guangdong 518036, P.R. China, Department of Geriatrics, Wuhan University, Renmin Hospital, Wuhan, Hubei 430060, P.R. China, Department of Immunology, School of Basic Medical Sciences, Wuhan University, Wuhan, Hubei 430071, P.R. China
Published online on: April 10, 2018 https://doi.org/10.3892/ol.2018.8446
Pages: 8611-8619
Copyright: © Qin et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

G9A, the primary histone methyltransferase (HMTase) for histone H3 lysine 9, is upregulated in numerous types of cancer and is critical for tumor cell proliferation. The present study aimed to investigate the G9A expression level in colorectal carcinoma (CRC) to evaluate the clinical significance of G9A in CRC. First, the present study detected the expression of G9A protein in 100 pairs of CRC specimens by immunohistochemistry staining and analyzed the correlations between G9A expression and pathological tumor features. It was found that G9A expression was increased markedly in CRC tumor specimens and the high expression was associated with tumor distant metastasis. Oncomine database analysis demonstrated an elevated expression level of G9A in various types of CRC. In total, 6 public available data sets from the Gene Expression Omnibus (GEO) were used and Gene set enrichment analysis (GSEA) was conducted. The results of the bioinformatics analysis demonstrated that high G9A expression was associated with American Joint Committee on Cancer staging, tumor differentiation, tumor relapse of CRC, and may serve a role in CRC cell proliferation. These findings suggested that G9A was overexpressed in CRC and involved in the tumorigenesis and distant metastasis of CRC. The expression level may also serve as a potential indicator for tumor recurrence in CRC. The present findings aided in the understanding of the crucial role of G9A in tumorigenesis and also offered novel ideas for CRC therapy.

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1	Rodríguez-Paredes M and Esteller M: Cancer epigenetics reaches mainstream oncology. Nat Med. 17:330–339. 2011. View Article : Google Scholar : PubMed/NCBI
2	Fraga MF, Ballestar E, Villar-Garea A, Boix-Chornet M, Espada J, Schotta G, Bonaldi T, Haydon C, Ropero S, Petrie K, et al: Loss of acetylation at Lys16 and trimethylation at Lys20 of histone H4 is a common hallmark of human cancer. Nat Genet. 37:391–400. 2005. View Article : Google Scholar : PubMed/NCBI
3	Wood LD, Parsons DW, Jones S, Lin J, Sjöblom T, Leary RJ, Shen D, Boca SM, Barber T, Ptak J, et al: The genomic landscapes of human breast and colorectal cancers. Science. 318:1108–1113. 2007. View Article : Google Scholar : PubMed/NCBI
4	Jemal A, Bray F, Center MM, Ferlay J, Ward E and Forman D: Global cancer statistics. CA Cancer J Clin. 61:69–90. 2011. View Article : Google Scholar : PubMed/NCBI
5	Carmona FJ and Esteller M: Moving closer to a prognostic DNA methylation signature in colon cancer. Clin Cancer Res. 17:1215–1217. 2011. View Article : Google Scholar : PubMed/NCBI
6	Irizarry RA, Ladd-Acosta C, Wen B, Wu Z, Montano C, Onyango P, Cui H, Gabo K, Rongione M, Webster M, et al: The human colon cancer methylome shows similar hypo- and hypermethylation at conserved tissue-specific CpG island shores. Nat Genet. 41:178–186. 2009. View Article : Google Scholar : PubMed/NCBI
7	Jiang X, Tan J, Li J, Kivimäe S, Yang X, Zhuang L, Lee PL, Chan MT, Stanton LW, Liu ET, et al: DACT3 is an epigenetic regulator of Wnt/beta-catenin signaling in colorectal cancer and is a therapeutic target of histone modifications. Cancer Cell. 13:529–541. 2008. View Article : Google Scholar : PubMed/NCBI
8	Fluge Ø, Gravdal K, Carlsen E, Vonen B, Kjellevold K, Refsum S, Lilleng R, Eide TJ, Halvorsen TB, Tveit KM, et al: Expression of EZH2 and Ki-67 in colorectal cancer and associations with treatment response and prognosis. Br J Cancer. 101:1282–1289. 2009. View Article : Google Scholar : PubMed/NCBI
9	Yamamoto S, Tateishi K, Kudo Y, Yamamoto K, Isagawa T, Nagae G, Nakatsuka T, Asaoka Y, Ijichi H, Hirata Y, et al: Histone demethylase KDM4C regulates sphere formation by mediating the cross talk between Wnt and Notch pathways in colonic cancer cells. Carcinogenesis. 34:2380–2388. 2013. View Article : Google Scholar : PubMed/NCBI
10	Shinkai Y and Tachibana M: H3K9 methyltransferase G9a and the related molecule GLP. Genes Dev. 25:781–788. 2011. View Article : Google Scholar : PubMed/NCBI
11	Dawson MA and Kouzarides T: Cancer epigenetics: From mechanism to therapy. Cell. 150:12–27. 2012. View Article : Google Scholar : PubMed/NCBI
12	Maze I, Covington HE III, Dietz DM, LaPlant Q, Renthal W, Russo SJ, Mechanic M, Mouzon E, Neve RL, Haggarty SJ, et al: Essential role of the histone methyltransferase G9a in cocaine-induced plasticity. Science. 327:213–216. 2010. View Article : Google Scholar : PubMed/NCBI
13	Thomas LR, Miyashita H, Cobb RM, Pierce S, Tachibana M, Hobeika E, Reth M, Shinkai Y and Oltz EM: Functional analysis of histone methyltransferase g9a in B and T lymphocytes. J Immunol. 181:485–493. 2008. View Article : Google Scholar : PubMed/NCBI
14	Katoh K, Yamazaki R, Onishi A, Sanuki R and Furukawa T: G9a histone methyltransferase activity in retinal progenitors is essential for proper differentiation and survival of mouse retinal cells. J Neurosci. 32:17658–17670. 2012. View Article : Google Scholar : PubMed/NCBI
15	Ueda J, Ho JC, Lee KL, Kitajima S, Yang H, Sun W, Fukuhara N, Zaiden N, Chan SL, Tachibana M, et al: The hypoxia-inducible epigenetic regulators Jmjd1a and G9a provide a mechanistic link between angiogenesis and tumor growth. Mol Cell Biol. 34:3702–3720. 2014. View Article : Google Scholar : PubMed/NCBI
16	Chen X, Skutt-Kakaria K, Davison J, Ou YL, Choi E, Malik P, Loeb K, Wood B, Georges G, Torok-Storb B and Paddison PJ: G9a/GLP-dependent histone H3K9me2 patterning during human hematopoietic stem cell lineage commitment. Genes Dev. 26:2499–2511. 2012. View Article : Google Scholar : PubMed/NCBI
17	Ke XX, Zhang D, Zhu S, Xia Q, Xiang Z and Cui H: Inhibition of H3K9 methyltransferase G9a repressed cell proliferation and induced autophagy in neuroblastoma cells. PLoS One. 9:e1069622014. View Article : Google Scholar : PubMed/NCBI
18	Huang J, Dorsey J, Chuikov S, Pérez-Burgos L, Zhang X, Jenuwein T, Reinberg D and Berger SL: G9a and Glp methylate lysine 373 in the tumor suppressor p53. J Biol Chem. 285:9636–9641. 2010. View Article : Google Scholar : PubMed/NCBI
19	Kondo Y, Shen L, Suzuki S, Kurokawa T, Masuko K, Tanaka Y, Kato H, Mizuno Y, Yokoe M, Sugauchi F, et al: Alterations of DNA methylation and histone modifications contribute to gene silencing in hepatocellular carcinomas. Hepatol Res. 37:974–983. 2007. View Article : Google Scholar : PubMed/NCBI
20	Kim Y, Kim YS, Kim DE, Lee JS, Song JH, Kim HG, Cho DH, Jeong SY, Jin DH, Jang SJ, et al: BIX-01294 induces autophagy-associated cell death via EHMT2/G9a dysfunction and intracellular reactive oxygen species production. Autophagy. 9:2126–2139. 2013. View Article : Google Scholar : PubMed/NCBI
21	Zhang J, He P, Xi Y, Geng M, Chen Y and Ding J: Down-regulation of G9a triggers DNA damage response and inhibits colorectal cancer cells proliferation. Oncotarget. 6:2917–2927. 2015.PubMed/NCBI
22	Edge SB and Compton CC: The American joint committee on cancer: The 7th edition of the AJCC cancer staging manual and the future of TNM. Ann Surg Oncol. 17:1471–1474. 2010. View Article : Google Scholar : PubMed/NCBI
23	Kyriakos M: The President's cancer, the Dukes classification, and confusion. Arch Pathol Lab Med. 109:1063–1066. 1985.PubMed/NCBI
24	Barresi V, Bonetti Reggiani L, Ieni A, Caruso RA and Tuccari G: Histological grading in colorectal cancer: New insights and perspectives. Histol Histopathol. 30:1059–1067. 2015.PubMed/NCBI
25	Zeng Z, Wu HX, Zhan N, Huang YB, Wang ZS, Yang GF, Wang P and Fu GH: Prognostic significance of USP10 as a tumor-associated marker in gastric carcinoma. Tumour Biol. 35:3845–3853. 2014. View Article : Google Scholar : PubMed/NCBI
26	Rhodes DR, Yu J, Shanker K, Deshpande N, Varambally R, Ghosh D, Barrette T, Pandey A and Chinnaiyan AM: ONCOMINE: A cancer microarray database and integrated data-mining platform. Neoplasia. 6:1–6. 2004. View Article : Google Scholar : PubMed/NCBI
27	Tripathi MK, Deane NG, Zhu J, An H, Mima S, Wang X, Padmanabhan S, Shi Z, Prodduturi N, Ciombor KK, et al: Nuclear factor of activated T-cell activity is associated with metastatic capacity in colon cancer. Cancer Res. 74:6947–6957. 2014. View Article : Google Scholar : PubMed/NCBI
28	Laibe S, Lagarde A, Ferrari A, Monges G, Birnbaum D and Olschwang S: COL2 Project: A seven-gene signature aggregates a subgroup of stage II colon cancers with stage III. OMICS. 16:560–565. 2012.PubMed/NCBI
29	Loboda A, Nebozhyn MV, Watters JW, Buser CA, Shaw PM, Huang PS, Van't Veer L, Tollenaar RA, Jackson DB, Agrawal D, et al: EMT is the dominant program in human colon cancer. BMC Med Genomics. 4:92011. View Article : Google Scholar : PubMed/NCBI
30	Smith JJ, Deane NG, Wu F, Merchant NB, Zhang B, Jiang A, Lu P, Johnson JC, Schmidt C, Bailey CE, et al: Experimentally derived metastasis gene expression profile predicts recurrence and death in patients with colon cancer. Gastroenterology. 138:958–968. 2010. View Article : Google Scholar : PubMed/NCBI
31	Freeman TJ, Smith JJ, Chen X, Washington MK, Roland JT, Means AL, Eschrich SA, Yeatman TJ, Deane NG and Beauchamp RD: Smad4-mediated signaling inhibits intestinal neoplasia by inhibiting expression of β-catenin. Gastroenterology. 142:562–571.e2. 2012. View Article : Google Scholar : PubMed/NCBI
32	Gröne J, Lenze D, Jurinovic V, Hummel M, Seidel H, Leder G, Beckmann G, Sommer A, Grützmann R, Pilarsky C, et al: Molecular profiles and clinical outcome of stage UICC II colon cancer patients. Int J Colorectal Dis. 26:847–858. 2011. View Article : Google Scholar : PubMed/NCBI
33	Kemper K, Versloot M, Cameron K, Colak S, de Sousa e Melo F, de Jong JH, Bleackley J, Vermeulen L, Versteeg R, Koster J and Medema JP: Mutations in the Ras-Raf Axis underlie the prognostic value of CD133 in colorectal cancer. Clin Cancer Res. 18:3132–3141. 2012. View Article : Google Scholar : PubMed/NCBI
34	de Sousa E, Melo F, Colak S, Buikhuisen J, Koster J, Cameron K, de Jong JH, Tuynman JB, Prasetyanti PR, Fessler E, van den Bergh SP, et al: Methylation of cancer-stem-cell-associated Wnt target genes predicts poor prognosis in colorectal cancer patients. Cell Stem Cell. 9:476–485. 2011. View Article : Google Scholar : PubMed/NCBI
35	Subramanian A, Tamayo P, Mootha VK, Mukherjee S, Ebert BL, Gillette MA, Paulovich A, Pomeroy SL, Golub TR, Lander ES and Mesirov JP: Gene set enrichment analysis: A knowledge-based approach for interpreting genome-wide expression profiles. Proc Natl Acad Sci USA. 102:15545–15550. 2005. View Article : Google Scholar : PubMed/NCBI
36	Mootha VK, Lindgren CM, Eriksson KF, Subramanian A, Sihag S, Lehar J, Puigserver P, Carlsson E, Ridderstråle M, Laurila E, et al: PGC-1alpha-responsive genes involved in oxidative phosphorylation are coordinately downregulated in human diabetes. Nat Genet. 34:267–273. 2003. View Article : Google Scholar : PubMed/NCBI
37	Cancer Genome Atlas Network: Comprehensive molecular characterization of human colon and rectal cancer. Nature. 487:330–337. 2012. View Article : Google Scholar : PubMed/NCBI
38	Kaiser S, Park YK, Franklin JL, Halberg RB, Yu M, Jessen WJ, Freudenberg J, Chen X, Haigis K, Jegga AG, et al: Transcriptional recapitulation and subversion of embryonic colon development by mouse colon tumor models and human colon cancer. Genome Biol. 8:R1312007. View Article : Google Scholar : PubMed/NCBI
39	Gaedcke J, Grade M, Jung K, Camps J, Jo P, Emons G, Gehoff A, Sax U, Schirmer M, Becker H, et al: Mutated KRAS results in overexpression of DUSP4, a MAP-kinase phosphatase, and SMYD3, a histone methyltransferase, in rectal carcinomas. Genes Chromosomes Cancer. 49:1024–1034. 2010. View Article : Google Scholar : PubMed/NCBI
40	Hong Y, Downey T, Eu KW, Koh PK and Cheah PY: A ‘metastasis-prone’ signature for early-stage mismatch-repair proficient sporadic colorectal cancer patients and its implications for possible therapeutics. Clin Exp Metastasis. 27:83–90. 2010. View Article : Google Scholar : PubMed/NCBI
41	Tachibana M, Sugimoto K, Nozaki M, Ueda J, Ohta T, Ohki M, Fukuda M, Takeda N, Niida H, Kato H and Shinkai Y: G9a histone methyltransferase plays a dominant role in euchromatic histone H3 lysine 9 methylation and is essential for early embryogenesis. Genes Dev. 16:1779–1791. 2002. View Article : Google Scholar : PubMed/NCBI
42	Cho HS, Kelly JD, Hayami S, Toyokawa G, Takawa M, Yoshimatsu M, Tsunoda T, Field HI, Neal DE, Ponder BA, et al: Enhanced expression of EHMT2 is involved in the proliferation of cancer cells through negative regulation of SIAH1. Neoplasia. 13:676–684. 2011. View Article : Google Scholar : PubMed/NCBI
43	Chen MW, Hua KT, Kao HJ, Chi CC, Wei LH, Johansson G, Shiah SG, Chen PS, Jeng YM, Cheng TY, et al: H3K9 histone methyltransferase G9a promotes lung cancer invasion and metastasis by silencing the cell adhesion molecule Ep-CAM. Cancer Res. 70:7830–7840. 2010. View Article : Google Scholar : PubMed/NCBI