Correlation between promoter methylation of the LDH‑C4 gene and DNMT expression in breast cancer and their prognostic significance

Zhang,Jiandong; Zhang,Fengxia; Zhang,Fengqin; Wu,Hua; Zhang,Bei; Wu,Xiangyun

doi:10.3892/ol.2021.13153

Correlation between promoter methylation of the LDH‑C4 gene and DNMT expression in breast cancer and their prognostic significance

Authors:
- Jiandong Zhang
- Fengxia Zhang
- Fengqin Zhang
- Hua Wu
- Bei Zhang
- Xiangyun Wu
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Affiliations: Clinical Laboratory, The Third Hospital of Hebei Medical University, Shijiazhuang, Hebei 050011, P.R. China, Nursing Department, Hengshui Health School, Hengshui, Hebei 050000, P.R. China, Pathology Department, Hengshui People's Hospital of Hebei Medical University, Hengshui, Hebei 050000, P.R. China
Published online on: December 1, 2021 https://doi.org/10.3892/ol.2021.13153
Article Number: 35

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Abstract

DNA methylation plays an important role in tumorigenesis and development. The potential of aberrant DNA methylation to act as a biomarker for tumor diagnosis and prognostic evaluation is currently being explored. Lactate dehydrogenase C4 (LDH‑C4) is a member of the cancer/testis antigen family that is expressed in a broad range of human tumor types, with particularly high expression patterns observed in lung cancer, melanoma and breast cancer. However, whether the methylation of the promoter region of LDH‑C4 can be used as a tumor marker and its association with prognosis remain poorly understood. The present study aimed to determine the potential of the methylation status of LDH‑C4 and DNA methyltransferase (DNMT) expression to be biological markers for the prognostic evaluation of breast cancer. Methylation‑specific PCR was conducted to evaluate alterations in the methylation levels of LDH‑C4. Immunohistochemical analysis was performed to assess the expression levels of DNMTs in breast cancer tissues. The association between the methylation status of LDH‑C4 or the expression of DNMTs, and clinical pathological parameters was also evaluated. The results of the present study revealed that the demethylation rate of LDH‑C4 in breast cancer tissues was significantly increased compared with that of adjacent tissues, and associations were identified between the demethylation of LDH‑C4 and the histological grade, estrogen receptor, progesterone receptor and HER‑2 status, and lymph node metastasis. The level of LDH‑C4 demethylation was negatively correlated with the expression of DNMTs. Demethylation of the LDH‑C4 promoter and DNMT expression predicted an unfavorable prognosis of patients with breast cancer. In addition, demethylation of the LDH‑C4 promoter, high expression of DNMT3a and DNMT3b, histological grade and lymph node metastasis were all discovered to be independent prognostic factors in patients with breast cancer. In conclusion, results of the present study indicated that the demethylation of LDH‑C4 and DNMT expression levels may be closely associated with the occurrence and development of breast cancer, in addition to lymph node metastasis. Thus, both may be used to assist the clinical evaluation of prognosis.

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1	Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A and Bray F: Global Cancer Statistics 2020: GLOBOCAN Estimates of Incidence and Mortality Worldwide for 36 Cancers in 185 Countries. CA Cancer J Clin. 71:209–249. 2021. View Article : Google Scholar : PubMed/NCBI
2	Reis-Filho JS and Pusztai L: Gene expression profiling in breast cancer: Classification, prognostication, and prediction. Lancet. 378:1812–1823. 2011. View Article : Google Scholar : PubMed/NCBI
3	Lnning PE: Breast cancer prognostication and prediction: Are we making progress. Ann Oncol. 18 (Suppl 8):viii3–7. 2007. View Article : Google Scholar : PubMed/NCBI
4	Shao Y, Sun X, He Y, Liu C and Liu H: Elevated Levels of Serum Tumor Markers CEA and CA15-3 Are Prognostic Parameters for Different Molecular Subtypes of Breast Cancer. PLoS One. 10:e01338302015. View Article : Google Scholar : PubMed/NCBI
5	Kong L, Du W, Cui Z, Wang L, Yang Z, Zhang H and Lin D: Expression of lactate dehydrogenase C in MDA MB 231 cells and its role in tumor invasion and migration. Mol Med Rep. 13:3533–3538. 2016. View Article : Google Scholar : PubMed/NCBI
6	Goldberg E, Eddy EM, Duan C and Odet F: LDHC: the ultimate testis-specific gene. J Androl. 31:86–94. 2010. View Article : Google Scholar : PubMed/NCBI
7	Woodford MR, Chen VZ, Backe SJ, Bratslavsky G and Mollapour M: Structural and functional regulation of lactate dehydrogenase-A in cancer. Future Med Chem. 12:439–455. 2020. View Article : Google Scholar : PubMed/NCBI
8	Tang H and Goldberg E: Homo sapiens lactate dehydrogenase c (Ldhc) gene expression in cancer cells is regulated by transcription factor Sp1, CREB, and CpG island methylation. J Androl. 30:157–167. 2009. View Article : Google Scholar : PubMed/NCBI
9	Tang H, Kung A and Goldberg E: Regulation of murine lactate dehydrogenase C (Ldhc) gene expression. Biol Reprod. 78:455–461. 2008. View Article : Google Scholar : PubMed/NCBI
10	Ding W, Chen G and Shi T: Integrative analysis identifies potential DNA methylation biomarkers for pan-cancer diagnosis and prognosis. Epigenetics. 14:67–80. 2019. View Article : Google Scholar : PubMed/NCBI
11	Jin B and Robertson KD: DNA methyltransferases, DNA damage repair, and cancer. Adv Exp Med Biol. 754:3–29. 2013. View Article : Google Scholar : PubMed/NCBI
12	Lam TW, Tong JH, To KF, Chan A, Liew CT, Lai PB and Wong N: Correlative Analysis of DNA Methyltransferase Expression and Promoter Hypermethylation of Tumor Suppressor Genes in Hepatocellular Carcinoma. Cancer Genomics Proteomics. 3:271–277. 2006.PubMed/NCBI
13	Mirza S, Sharma G, Parshad R, Gupta SD, Pandya P and Ralhan R: Expression of DNA methyltransferases in breast cancer patients and to analyze the effect of natural compounds on DNA methyltransferases and associated proteins. J Breast Cancer. 16:23–31. 2013. View Article : Google Scholar : PubMed/NCBI
14	Aman NA, Doukoure B, Koffi KD, Koui BS, Traore ZC, Kouyate M, Toure I and Effi AB: Immunohistochemical Evaluation of Ki-67 and Comparison with Clinicopathologic Factors in Breast Carcinomas. Asian Pac J Cancer Prev. 20:73–79. 2019. View Article : Google Scholar : PubMed/NCBI
15	Parambil NA, Philip S, Tripathy JP, Philip PM, Duraisamy K and Balasubramanian S: Community engaged breast cancer screening program in Kannur District, Kerala, India: A ray of hope for early diagnosis and treatment. Indian J Cancer. 56:222–227. 2019. View Article : Google Scholar : PubMed/NCBI
16	Banin Hirata BK, Oda JM, Losi Guembarovski R, Ariza CB, de Oliveira CE and Watanabe MA: Molecular markers for breast cancer: prediction on tumor behavior. Dis Markers. 2014.5131582014. PubMed/NCBI
17	Duan C and Goldberg E: Inhibition of lactate dehydrogenase C4 (LDH-C4) blocks capacitation of mouse sperm in vitro. Cytogenet Genome Res. 103:352–359. 2003. View Article : Google Scholar : PubMed/NCBI
18	Hogrefe HH, Kaumaya PT and Goldberg E: Immunogenicity of synthetic peptides corresponding to flexible and antibody-accessible segments of mouse lactate dehydrogenase (LDH)-C4. J Biol. 264:10513–10519. 1989.PubMed/NCBI
19	Grunwald C, Koslowski M, Arsiray T, Dhaene K, Praet M, Victor A, Morresi-Hauf A, Lindner M, Passlick B, Lehr HA, et al: Expression of multiple epigenetically regulated cancer/germline genes in non-small cell lung cancer. Int J Cancer. 118:2522–2528. 2006. View Article : Google Scholar : PubMed/NCBI
20	Chen L, Wu Q, Xu X, Yang C, You J, Chen F and Zeng Y: Cancer/testis antigen LDHC promotes proliferation and metastasis by activating the PI3K/Akt/GSK-3β-signaling pathway and the in lung adenocarcinoma. Exp Cell Res. 398:1124142021. View Article : Google Scholar : PubMed/NCBI
21	Cui Z and Chen Y, Hu M, Lin Y, Zhang S, Kong L and Chen Y: Diagnostic and prognostic value of the cancer-testis antigen lactate dehydrogenase C4 in breast cancer. Clin Chim Acta. 503:203–209. 2020. View Article : Google Scholar : PubMed/NCBI
22	Hua Y, Liang C, Zhu J, Miao C, Yu Y, Xu A, Zhang J, Li P, Li S, Bao M, et al: Expression of lactate dehydrogenase C correlates with poor prognosis in renal cell carcinoma. Tumour Biol. 39:10104283176959682017. View Article : Google Scholar : PubMed/NCBI
23	Kroft TL, Jethanandani P, McLean DJ and Goldberg E: Methylation of CpG dinucleotides alters binding and silences testis-specific transcription directed by the mouse lactate dehydrogenase C promoter. Biol Reprod. 65:1522–1527. 2001. View Article : Google Scholar : PubMed/NCBI
24	Hervouet E, Peixoto P, Delage-Mourroux R, Boyer-Guittaut M and Cartron PF: Specific or not specific recruitment of DNMTs for DNA methylation, an epigenetic dilemma. Clin Epigenetics. 10:172018. View Article : Google Scholar : PubMed/NCBI
25	He M, Fan J, Jiang R, Tang WX and Wang ZW: Expression of DNMTs and genomic DNA methylation in gastric signet ring cell carcinoma. Mol Med Rep. 8:942–948. 2013. View Article : Google Scholar : PubMed/NCBI
26	Supic G, Kozomara R, Zeljic K, Jovic N and Magic Z: Prognostic value of the DNMTs mRNA expression and genetic polymorphisms on the clinical outcome in oral cancer patients. Clin Oral Investig. 21:173–182. 2017. View Article : Google Scholar : PubMed/NCBI
27	Wu J, Shuang Z, Zhao J, Tang H, Liu P, Zhang L, Xie X and Xiao X: Linc00152 promotes tumorigenesis by regulating DNMTs in triple-negative breast cancer. Biomed Pharmacother. 97:1275–1281. 2018. View Article : Google Scholar : PubMed/NCBI
28	Turek-Plewa J and Jagodziński PP: The role of mammalian DNA methyltransferases in the regulation of gene expression. Cell Mol Biol Lett. 10:631–647. 2005.PubMed/NCBI
29	Jahangiri R, Jamialahmadi K, Gharib M, Emami Razavi A and Mosaffa F: Expression and clinicopathological significance of DNA methyltransferase 1, 3A and 3B in tamoxifen-treated breast cancer patients. Gene. 685:24–31. 2019. View Article : Google Scholar : PubMed/NCBI