Differential expression of tescalcin by modification of promoter methylation controls cell survival in gastric cancer cells

  • Authors:
    • Tae Woo Kim
    • Seung Ro Han
    • Jong‑Tae Kim
    • Seung‑Min Yoo
    • Myung‑Shin Lee
    • Seung‑Hoon Lee
    • Yun Hee Kang
    • Hee Gu Lee
  • View Affiliations

  • Published online on: April 4, 2019     https://doi.org/10.3892/or.2019.7099
  • Pages: 3464-3474
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Abstract

The EF‑hand calcium binding protein tescalcin (TESC) is highly expressed in various human and mouse cancer tissues and is therefore considered a potential oncogene. However, the underlying mechanism that governs TESC expression remains unclear. Emerging evidence suggests that TESC expression is under epigenetic regulation. In the present study, the relationship between the epigenetic modification and gene expression of TESC in gastric cancer was investigated. To evaluate the relationship between the methylation and expression of TESC in gastric cancer, the methylation status of CpG sites in the TESC promoter was analyzed using microarray with the Illumina Human Methylation27 BeadChip (HumanMethylation27_270596_v.1.2), gene profiles from the NCBI Dataset that revealed demethylated status were acquired, and real‑time methylation‑specific PCR (MSP) in gastric cancer cells was conducted. In the present study, it was demonstrated that the hypermethylation of TESC led to the downregulation of TESC mRNA/protein expression. In addition, 5‑aza‑2c‑deoxycytidine (5'‑aza‑dC) restored TESC expression in the tested gastric cancer cells except for SNU‑620 cells. ChIP assay further revealed that the methylation of the TESC promoter was associated with methyl‑CpG binding domain protein (MBD)1, histone deacetylase (HDAC)2, and Oct‑1 and that treatment with 5'‑aza‑dC facilitated the dissociation of MBD1, HDAC2, and Oct‑1 from the promoter of TESC. Moreover, silencing of TESC increased MBD1 expression and decreased the H3K4me2/3 level, thereby causing transcriptional repression and suppression of cell survival in NCI‑N87 cells; conversely, overexpression of TESC downregulated MBD1 expression and upregulated the H3K4me2 level associated with active transcription in SNU‑638 cells. These results indicated that the differential expression of TESC via the modification status of the promoter and histone methylation controled cell survival in gastric cancer cells. Overall, the present study provided a novel therapeutic strategy for gastric cancer.

References

1 

Takamatsu G, Katagiri C, Tomoyuki T, Shimizu-Okabe C, Nakamura W, Nakamura-Higa M, Hayakawa T, Wakabayashi S, Kondo T, Takayama C, et al: Tescalcin is a potential target of class Ihistone deacetylase inhibitors in neurons. Biochem Biophys Res Commun. 482:1327–1333. 2017. View Article : Google Scholar : PubMed/NCBI

2 

Mailänder J, Müller-Esterl W and Dedio J: Human homolog of mouse tescalcin associates with Na+/H+ exchanger type-1. FEBS Lett. 507:331–335. 2001. View Article : Google Scholar : PubMed/NCBI

3 

Malo ME and Fliegel L: Physiological role and regulation of the Na+/H+ exchanger. Can J Physiol Pharmacol. 84:1081–1095. 2006. View Article : Google Scholar : PubMed/NCBI

4 

Loo SY, Chang MK, Chua CS, Kumar AP, Pervaiz S and Clement MV: NHE-1: A promising target for novel anti-cancer therapeutics. Curr Pharm Des. 18:1372–1382. 2012. View Article : Google Scholar : PubMed/NCBI

5 

Fan J, Xing Y, Wen X, Jia R, Ni H, He J, Ding X, Pan H, Qian G, Ge S, et al: Long non-coding RNA ROR decoys gene-specific histone methylation to promote tumorigenesis. Genome Biol. 16:1392015. View Article : Google Scholar : PubMed/NCBI

6 

Kang YH, Han SR, Kim JT, Lee SJ, Yeom YI, Min JK, Lee CH, Kim JW, Yoon SR, Yoon DY, et al: The EF-hand calcium-binding protein tescalcin is a potential oncotarget in colorectal cancer. Oncotarget. 5:2149–2160. 2014. View Article : Google Scholar : PubMed/NCBI

7 

Kang J, Kang YH, Oh BM, Uhm TG, Park SY, Kim TW, Han SR, Lee SJ, Lee Y and Lee HG: Tescalcin expression contributes to invasive and metastatic activity in colorectal cancer. Tumour Biol. 37:13843–13853. 2016. View Article : Google Scholar : PubMed/NCBI

8 

Levay K and Slepak VZ: Tescalcin is an essential factor in megakaryocytic differentiation associated with Ets family gene expression. J Clin Invest. 117:2672–2683. 2007. View Article : Google Scholar : PubMed/NCBI

9 

Seth A, Ascione R, Fisher RJ, Mavrothalassitis GJ, Bhat NK and Papas TS: The ets gene family. Cell Growth Differ. 3:327–334. 1992.PubMed/NCBI

10 

Wasylyk B, Hahn SL and Giovane A: The Ets family of transcription factors. Eur J Biochem. 211:7–18. 1993. View Article : Google Scholar : PubMed/NCBI

11 

Oikawa T and Yamada T: Molecular biology of the Ets family of transcription factors. Gene. 303:11–34. 2003. View Article : Google Scholar : PubMed/NCBI

12 

Seth A and Watson DK: ETS transcription factors and their emerging roles in human cancer. Eur J Cancer. 41:2462–2478. 2005. View Article : Google Scholar : PubMed/NCBI

13 

Hogart A, Lichtenberg J, Ajay SS, Anderson S; NIH Intramural Sequencing Center, ; Margulies EH and Bodine DM: Genome-wide DNA methylation profiles in hematopoietic stem and progenitor cells reveal overrepresentation of ETS transcription factor binding sites. Genome Res. 22:1407–1418. 2012. View Article : Google Scholar : PubMed/NCBI

14 

Schones DE and Zhao K: Genome-wide approaches to studying chromatin modifications. Nat Rev Genet. 9:179–191. 2008. View Article : Google Scholar : PubMed/NCBI

15 

Liu B, Tahk S, Yee KM, Fan G and Shuai K: The ligase PIAS1 restricts natural regulatory T cell differentiation by epigenetic repression. Science. 330:521–525. 2010. View Article : Google Scholar : PubMed/NCBI

16 

Ling ZQ, Tanaka A, Li P, Nakayama T, Fujiyama Y, Hattori T and Sugihara H: Microsatellite instability with promoter methylation and silencing of hMLH1 can regionally occur during progression of gastric carcinoma. Cancer Lett. 297:244–251. 2010. View Article : Google Scholar : PubMed/NCBI

17 

Qu Y, Dang S and Hou P: Gene methylation in gastric cancer. Clin Chim Acta. 424:53–65. 2013. View Article : Google Scholar : PubMed/NCBI

18 

Yamamoto E, Suzuki H, Takamaru H, Yamamoto H, Toyota M and Shinomura Y: Role of DNA methylation in the development of diffuse-type gastric cancer. Digestion. 83:241–249. 2011. View Article : Google Scholar : PubMed/NCBI

19 

Yu JS, Koujak S, Nagase S, Li CM, Su T, Wang X, Keniry M, Memeo L, Rojtman A, Mansukhani M, et al: PCDH8, the human homolog of PAPC, is a candidate tumor suppressor of breast cancer. Oncogene. 27:4657–4665. 2008. View Article : Google Scholar : PubMed/NCBI

20 

Ai L, Kim WJ, Kim TY, Fields CR, Massoll NA, Robertson KD and Brown KD: Epigenetic silencing of the tumor suppressor cystatin M occurs during breast cancer progression. Cancer Res. 66:7899–7909. 2006. View Article : Google Scholar : PubMed/NCBI

21 

Wolf I, O'Kelly J, Rubinek T, Tong M, Nguyen A, Lin BT, Tai HH, Karlan BY and Koeffler HP: 15-hydroxyprostaglandin dehydrogenase is a tumor suppressor of human breast cancer. Cancer Res. 66:7818–7823. 2006. View Article : Google Scholar : PubMed/NCBI

22 

Hendrich B and Tweedie S: The methyl-CpG binding domain and the evolving role of DNA methylation in animals. Trends Genet. 19:269–277. 2003. View Article : Google Scholar : PubMed/NCBI

23 

Hendrich B and Bird A: Identification and characterization of a family of mammalian methyl-CpG binding proteins. Mol Cell Biol. 18:6538–6547. 1998. View Article : Google Scholar : PubMed/NCBI

24 

Ballestar E and Esteller M: Methyl-CpG-binding proteins in cancer: Blaming the DNA methylation messenger. Biochem Cell Biol. 83:374–384. 2005. View Article : Google Scholar : PubMed/NCBI

25 

Sansom OJ, Maddison K and Clarke AR: Mechanisms of disease: Methyl-binding domain proteins as potential therapeutic targets in cancer. Nat Clin Pract Oncol. 4:305–315. 2007. View Article : Google Scholar : PubMed/NCBI

26 

Jørgensen HF, Ben-Porath I and Bird AP: Mbd1 is recruited to both methylated and nonmethylated CpGs via distinct DNA binding domains. Mol Cell Biol. 24:3387–3395. 2004. View Article : Google Scholar : PubMed/NCBI

27 

Liu H, Jin G, Wang H, Wu W, Liu Y, Qian J, Fan W, Ma H, Miao R, Hu Z, et al: Methyl-CpG binding domain 1 gene polymorphisms and lung cancer risk in a Chinese population. Biomarkers. 13:607–617. 2008. View Article : Google Scholar : PubMed/NCBI

28 

Wang J, Tai LS, Tzang CH, Fong WF, Guan XY and Yang M: 1p31, 7q21 and 18q21 chromosomal aberrations and candidate genes in acquired vinblastine resistance of human cervical carcinoma KB cells. Oncol Rep. 19:1155–1164. 2008.PubMed/NCBI

29 

Monnier P, Martinet C, Pontis J, Stancheva I, Ait-Si-Ali S and Dandolo L: H19 lncRNA controls gene expression of the Imprinted Gene Network by recruiting MBD1. Proc Natl Acad Sci USA. 110:20693–20698. 2013. View Article : Google Scholar : PubMed/NCBI

30 

Wang P, Lin C, Smith ER, Guo H, Sanderson BW, Wu M, Gogol M, Alexander T, Seidel C, Wiedemann LM, et al: Global analysis of H3K4 methylation defines MLL family member targets and points to a role for MLL1-mediated H3K4 methylation in the regulation of transcriptional initiation by RNA polymerase II. Mol Cell Biol. 29:6074–6085. 2009. View Article : Google Scholar : PubMed/NCBI

31 

Zheng YG, Wu J, Chen Z and Goodman M: Chemical regulation of epigenetic modifications: Opportunities for new cancer therapy. Med Res Rev. 28:645–687. 2008. View Article : Google Scholar : PubMed/NCBI

32 

Livak KJ and Schmittgen TD: Analysis of relative gene expression data using real-time quantitative PCR and the 2−ΔΔCT method. Methods. 25:402–408. 2001. View Article : Google Scholar : PubMed/NCBI

33 

Gibney ER and Nolan CM: Epigenetics and gene expression. Heredity. 105:4–13. 2010. View Article : Google Scholar : PubMed/NCBI

34 

Kulis M and Esteller M: DNA methylation and cancer. Adv Genet. 70:27–56. 2010. View Article : Google Scholar : PubMed/NCBI

35 

Nile CJ, Read RC, Akil M, Duff GW and Wilson AG: Methylation status of a single CpG site in the IL6 promoter is related to IL6 messenger RNA levels and rheumatoid arthritis. Arthritis Rheum. 58:2686–2693. 2008. View Article : Google Scholar : PubMed/NCBI

36 

Prokhortchouk E and Hendrich B: Methyl-CpG binding proteins and cancer: Are MeCpGs more important than MBDs? Oncogene. 21:5394–5399. 2002. View Article : Google Scholar : PubMed/NCBI

37 

Jones PL, Veenstra GJ, Wade PA, Vermaak D, Kass SU, Landsberger N, Strouboulis J and Wolffe AP: Methylated DNA and MeCP2 recruit histone deacetylase to repress transcription. Nat Genet. 19:187–191. 1998. View Article : Google Scholar : PubMed/NCBI

38 

Ng HH, Zhang Y, Hendrich B, Johnson CA, Turner BM, Erdjument-Bromage H, Tempst P, Reinberg D and Bird A: MBD2 is a transcriptional repressor belonging to the MeCP1 histone deacetylase complex. Nat Genet. 23:58–61. 1999. View Article : Google Scholar : PubMed/NCBI

39 

Clark SJ, Harrison J and Molloy PL: Sp1 binding is inhibited by mCpmCpG methylation. Gene. 195:67–71. 1997. View Article : Google Scholar : PubMed/NCBI

40 

Kim TW, Lee SJ, Oh BM, Lee H, Uhm TG, Min JK, Park YJ, Yoon SR, Kim BY, Kim JW, et al: Epigenetic modification of TLR4 promotes activation of NF-κB by regulating methyl-CpG-binding domain protein 2 and Sp1 in gastric cancer. Oncotarget. 7:4195–4209. 2016.PubMed/NCBI

41 

Murayama A, Sakura K, Nakama M, Yasuzawa-Tanaka K, Fujita E, Tateishi Y, Wang Y, Ushijima T, Baba T, Shibuya K, et al: A specific CpG site demethylation in the human interleukin 2 gene promoter is an epigenetic memory. EMBO J. 25:1081–1092. 2006. View Article : Google Scholar : PubMed/NCBI

42 

Perera EM, Bao Y, Kos L and Berkovitz G: Structural and functional characterization of the mouse tescalcin promoter. Gene. 464:50–62. 2010. View Article : Google Scholar : PubMed/NCBI

43 

Stein L, Rothschild J, Luce J, Cowell JK, Thomas G, Bogdanova TI, Tronko MD and Hawthorn L: Copy number and gene expression alterations in radiation-induced papillary thyroid carcinoma from chernobyl pediatric patients. Thyroid. 20:475–487. 2010. View Article : Google Scholar : PubMed/NCBI

44 

Man CH, Lam SS, Sun MK, Chow HC, Gill H, Kwong YL and Leung AY: A novel tescalcin-sodium/hydrogen exchange axis underlying sorafenib resistance in FLT3-ITD+ AML. Blood. 123:2530–2539. 2014. View Article : Google Scholar : PubMed/NCBI

45 

Qureshi SA, Bashir MU and Yaqinuddin A: Utility of DNA methylation markers for diagnosing cancer. Int J Surg. 8:194–198. 2010. View Article : Google Scholar : PubMed/NCBI

46 

Kim TW, Kim B, Kim JH, Kang S, Park SB, Jeong G, Kang HS and Kim SJ: Nuclear-encoded mitochondrial MTO1 and MRPL41 are regulated in an opposite epigenetic mode based on estrogen receptor status in breast cancer. BMC Cancer. 13:5022013. View Article : Google Scholar : PubMed/NCBI

47 

Chen B, Zeng C, Ye Y, Wu D, Mu Z, Liu J, Xie Y and Wu H: Promoter methylation of TCF21 may repress autophagy in the progression of lung cancer. J Cell Commun Signal. 12:423–432. 2018. View Article : Google Scholar : PubMed/NCBI

48 

Wang Y, He T, Herman JG, Linghu E, Yang Y, Fuks F, Zhou F, Song L and Guo M: Methylation of ZNF331 is an independent prognostic marker of colorectal cancer and promotes colorectal cancer growth. Clin Epigenetics. 9:1152017. View Article : Google Scholar : PubMed/NCBI

49 

Solomon O, Yousefi P, Huen K, Gunier RB, Escudero-Fung M, Barcellos LF, Eskenazi B and Holland N: Prenatal phthalate exposure and altered patterns of DNA methylation in cord blood. Environ Mol Mutagen. 58:398–410. 2017. View Article : Google Scholar : PubMed/NCBI

50 

Han KM, Won E, Kang J, Choi S, Kim A, Lee MS, Tae WS and Ham BJ: TESC gene-regulating genetic variant (rs7294919) affects hippocampal subfield volumes and parahippocampal cingulum white matter integrity in major depressive disorder. J Psychiatr Res. 93:20–29. 2017. View Article : Google Scholar : PubMed/NCBI

51 

Delcuve GP, Khan DH and Davie JR: Roles of histone deacetylases in epigenetic regulation: emerging paradigms from studies with inhibitors. Clin Epigenetics. 4:52012. View Article : Google Scholar : PubMed/NCBI

52 

Sarkar S, Abujamra AL, Loew JE, Forman LW, Perrine SP and Faller DV: Histone deacetylase inhibitors reverse CpG methylation by regulating DNMT1 through ERK signaling. Anticancer Res. 31:2723–2732. 2011.PubMed/NCBI

53 

Campanero MR, Armstrong MI and Flemington EK: CpG methylation as a mechanism for the regulation of E2F activity. Proc Natl Acad Sci USA. 97:6481–6486. 2000. View Article : Google Scholar : PubMed/NCBI

54 

Tian HP, Lun SM, Huang HJ, He R, Kong PZ, Wang QS, Li XQ and Feng YM: DNA methylation affects the SP1-regulated transcription of FOXF2 in breast cancer cells. J Biol Chem. 290:19173–19183. 2015. View Article : Google Scholar : PubMed/NCBI

55 

Garrity PA, Chen D, Rothenberg EV and Wold BJ: Interleukin-2 transcription is regulated in vivo at the level of coordinated binding of both constitutive and regulated factors. Mol Cell Biol. 14:2159–2169. 1994. View Article : Google Scholar : PubMed/NCBI

56 

Iguchi-Ariga SM and Schaffner W: CpG methylation of the cAMP-responsive enhancer/promoter sequence TGACGTCA abolishes specific factor binding as well as transcriptional activation. Genes Dev. 3:612–619. 1989. View Article : Google Scholar : PubMed/NCBI

57 

Nair SS, Coolen MW, Stirzaker C, Song JZ, Statham AL, Strbenac D, Robinson MD and Clark SJ: Comparison of methyl-DNA immunoprecipitation (MeDIP) and methyl-CpG binding domain (MBD) protein capture for genome-wide DNA methylation analysis reveal CpG sequence coverage bias. Epigenetics. 6:34–44. 2011. View Article : Google Scholar : PubMed/NCBI

58 

Fujita N, Takebayashi S, Okumura K, Kudo S, Chiba T, Saya H and Nakao M: Methylation-mediated transcriptional silencing in euchromatin by methyl-CpG binding protein MBD1 isoforms. Mol Cell Biol. 19:6415–6426. 1999. View Article : Google Scholar : PubMed/NCBI

59 

Patra SK, Patra A, Zhao H, Carroll P and Dahiya R: Methyl-CpG-DNA binding proteins in human prostate cancer: expression of CXXC sequence containing MBD1 and repression of MBD2 and MeCP2. Biochem Biophys Res Commun. 302:759–766. 2003. View Article : Google Scholar : PubMed/NCBI

60 

Bird AP and Wolffe AP: Methylation-induced repression-belts, braces, and chromatin. Cell. 99:451–454. 1999. View Article : Google Scholar : PubMed/NCBI

61 

Dhasarathy A and Wade PA: The MBD protein family - reading an epigenetic mark? Mutat Res. 647:39–43. 2008. View Article : Google Scholar : PubMed/NCBI

62 

Ng HH, Xu RM, Zhang Y and Struhl K: Ubiquitination of histone H2B by Rad6 is required for efficient Dot1-mediated methylation of histone H3 lysine 79. J Biol Chem. 277:34655–34657. 2002. View Article : Google Scholar : PubMed/NCBI

63 

Fernandez-Capetillo O, Allis CD and Nussenzweig A: Phosphorylation of histone H2B at DNA double-strand breaks. J Exp Med. 199:1671–1677. 2004. View Article : Google Scholar : PubMed/NCBI

64 

Tamagawa H, Oshima T, Shiozawa M, Morinaga S, Nakamura Y, Yoshihara M, Sakuma Y, Kameda Y, Akaike M, Masuda M, et al: The global histone modification pattern correlates with overall survival in metachronous liver metastasis of colorectal cancer. Oncol Rep. 27:637–642. 2012.PubMed/NCBI

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APA
Kim, T.W., Han, S.R., Kim, J., Yoo, S., Lee, M., Lee, S. ... Lee, H.G. (2019). Differential expression of tescalcin by modification of promoter methylation controls cell survival in gastric cancer cells. Oncology Reports, 41, 3464-3474. https://doi.org/10.3892/or.2019.7099
MLA
Kim, T. W., Han, S. R., Kim, J., Yoo, S., Lee, M., Lee, S., Kang, Y. H., Lee, H. G."Differential expression of tescalcin by modification of promoter methylation controls cell survival in gastric cancer cells". Oncology Reports 41.6 (2019): 3464-3474.
Chicago
Kim, T. W., Han, S. R., Kim, J., Yoo, S., Lee, M., Lee, S., Kang, Y. H., Lee, H. G."Differential expression of tescalcin by modification of promoter methylation controls cell survival in gastric cancer cells". Oncology Reports 41, no. 6 (2019): 3464-3474. https://doi.org/10.3892/or.2019.7099