Skip to main content
Top
Published in: Discover Oncology 1/2024

Open Access 01-12-2024 | Research

Correlation of DNA methylation of DNMT3A and TET2 with oral squamous cell carcinoma

Authors: Xueming Li, Zaikun Li, Qingxi Gao, Yanan Peng, Yang Yu, Tenglong Hu, Wei Wang

Published in: Discover Oncology | Issue 1/2024

Login to get access

Abstract

Oral squamous cell carcinoma (OSCC) is the sixth most common malignancy worldwide. Abnormal epigenetic modifications, including DNA methylation, are hallmarks of cancer and implicated in the development of various tumors. DNA methylation is catalyzed by the DNA methyltransferase and ten-eleven translocation dioxygenase families, with DNMT3A and TET2 being the most widely studied members, respectively. The correlation of methylation β values and clinical features was conducted in patients with OSCC in The Cancer Genome Atlas database. DNA methylation and protein expression levels of DNMT3A and TET2 in tissues were analyzed with methylation-specific polymerase chain reaction (MSP) and western blotting. To evaluate the effects of DNMT3A and TET2 on the biological characteristics of OSCC, cell proliferation was assessed with 5-ethynyl-2'-deoxyuridine, and cell migration capacity was quantified with wound healing and transwell assays. A survival analysis was performed with the Kaplan–Meier approach. The correlation between different methylation β values and clinical features was revealed. MSP revealed varying methylation degrees of DNMT3A and TET2 in OSCC tissues. Furthermore, western blotting showed that the protein expression levels were significantly different in cancer and surrounding healthy tissue samples. In vitro experiments demonstrated that DNMT3A knockdown and TET2 overexpression could inhibit the proliferation and migration of OSCC. Survival analysis revealed that patients with high DNMT3A methylation levels showed higher survival rates.
Literature
1.
go back to reference Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–12.PubMedCrossRef Sung H, Ferlay J, Siegel RL, Laversanne M, Soerjomataram I, Jemal A, et al. Global cancer statistics 2020: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2021;71:209–12.PubMedCrossRef
2.
5.
go back to reference Bondarev N, Ivanenko K, Khabusheva E, Lebedev T, Manukhov I, Prassolov V. MGL S3 chimeric enzyme drives apoptotic death of EGFR-dependent cancer cells through ERK downregulation. Int J Mol Sci. 2022;23:12807.PubMedPubMedCentralCrossRef Bondarev N, Ivanenko K, Khabusheva E, Lebedev T, Manukhov I, Prassolov V. MGL S3 chimeric enzyme drives apoptotic death of EGFR-dependent cancer cells through ERK downregulation. Int J Mol Sci. 2022;23:12807.PubMedPubMedCentralCrossRef
6.
go back to reference Li Y, Gan Y, Liu J, Li J, Zhou Z, Tian R, et al. Downregulation of MEIS1 mediated by ELFN1-AS1/EZH2/DNMT3a axis promotes tumorigenesis and oxaliplatin resistance in colorectal cancer. Signal Transduct Target Ther. 2022;7:87.PubMedPubMedCentralCrossRef Li Y, Gan Y, Liu J, Li J, Zhou Z, Tian R, et al. Downregulation of MEIS1 mediated by ELFN1-AS1/EZH2/DNMT3a axis promotes tumorigenesis and oxaliplatin resistance in colorectal cancer. Signal Transduct Target Ther. 2022;7:87.PubMedPubMedCentralCrossRef
7.
go back to reference Liang Y, Cen J, Huang Y, Fang Y, Wang Y, Shu G, et al. CircNTNG1 inhibits renal cell carcinoma progression via HOXA5-mediated epigenetic silencing of Slug. Mol Cancer. 2022;21:224.PubMedPubMedCentralCrossRef Liang Y, Cen J, Huang Y, Fang Y, Wang Y, Shu G, et al. CircNTNG1 inhibits renal cell carcinoma progression via HOXA5-mediated epigenetic silencing of Slug. Mol Cancer. 2022;21:224.PubMedPubMedCentralCrossRef
8.
go back to reference He J, Dong C, Zhang H, Jiang Y, Liu T, Man X. The oncogenic role of TFAP2A in bladder urothelial carcinoma via a novel long noncoding RNA TPRG1-AS1/DNMT3A/CRTAC1 axis. Cell Signal. 2023;102:110527.PubMedCrossRef He J, Dong C, Zhang H, Jiang Y, Liu T, Man X. The oncogenic role of TFAP2A in bladder urothelial carcinoma via a novel long noncoding RNA TPRG1-AS1/DNMT3A/CRTAC1 axis. Cell Signal. 2023;102:110527.PubMedCrossRef
9.
go back to reference Lu W, Lu T, Wei X. Downregulation of DNMT3a expression increases miR-182-induced apoptosis of ovarian cancer through caspase-3 and caspase-9-mediated apoptosis and DNA damage response. Oncol Rep. 2016;36:3597–603.PubMedCrossRef Lu W, Lu T, Wei X. Downregulation of DNMT3a expression increases miR-182-induced apoptosis of ovarian cancer through caspase-3 and caspase-9-mediated apoptosis and DNA damage response. Oncol Rep. 2016;36:3597–603.PubMedCrossRef
11.
go back to reference Zhou Y, Yang Z, Zhang H, Li H, Zhang M, Wang H, et al. DNMT3A facilitates colorectal cancer progression via regulating DAB2IP mediated MEK/ERK activation. Biochim Biophys Acta Mol Basis Dis. 2022;1868:166353.PubMedCrossRef Zhou Y, Yang Z, Zhang H, Li H, Zhang M, Wang H, et al. DNMT3A facilitates colorectal cancer progression via regulating DAB2IP mediated MEK/ERK activation. Biochim Biophys Acta Mol Basis Dis. 2022;1868:166353.PubMedCrossRef
12.
go back to reference Zhao Z, Song J, Tang B, Fang S, Zhang D, Zheng L, et al. CircSOD2 induced epigenetic alteration drives hepatocellular carcinoma progression through activating JAK2/STAT3 signaling pathway. J Exp Clin Cancer Res. 2020;39:259.PubMedPubMedCentralCrossRef Zhao Z, Song J, Tang B, Fang S, Zhang D, Zheng L, et al. CircSOD2 induced epigenetic alteration drives hepatocellular carcinoma progression through activating JAK2/STAT3 signaling pathway. J Exp Clin Cancer Res. 2020;39:259.PubMedPubMedCentralCrossRef
13.
go back to reference Quivoron C, Couronné L, Della Valle V, Lopez CK, Plo I, Wagner-Ballon O, et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell. 2011;20:25–33.PubMedCrossRef Quivoron C, Couronné L, Della Valle V, Lopez CK, Plo I, Wagner-Ballon O, et al. TET2 inactivation results in pleiotropic hematopoietic abnormalities in mouse and is a recurrent event during human lymphomagenesis. Cancer Cell. 2011;20:25–33.PubMedCrossRef
14.
go back to reference Álvarez-Errico D, Vento-Tormo R, Sieweke M, Ballestar E. Epigenetic control of myeloid cell differentiation, identity and function. Nat Rev Immunol. 2015;15:7–1.PubMedCrossRef Álvarez-Errico D, Vento-Tormo R, Sieweke M, Ballestar E. Epigenetic control of myeloid cell differentiation, identity and function. Nat Rev Immunol. 2015;15:7–1.PubMedCrossRef
15.
go back to reference Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Massé A, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289–92.PubMedCrossRef Delhommeau F, Dupont S, Della Valle V, James C, Trannoy S, Massé A, et al. Mutation in TET2 in myeloid cancers. N Engl J Med. 2009;360:2289–92.PubMedCrossRef
16.
go back to reference Ma S, Wan X, Deng Z, Shi L, Hao C, Zhou Z, et al. Epigenetic regulator CXXC5 recruits DNA demethylase Tet2 to regulate TLR7/9-elicited IFN response in pDCs. J Exp Med. 2017;214:1471–81.PubMedPubMedCentralCrossRef Ma S, Wan X, Deng Z, Shi L, Hao C, Zhou Z, et al. Epigenetic regulator CXXC5 recruits DNA demethylase Tet2 to regulate TLR7/9-elicited IFN response in pDCs. J Exp Med. 2017;214:1471–81.PubMedPubMedCentralCrossRef
17.
go back to reference Zhang Q, Zhao K, Shen Q, Han Y, Gu Y, Li X, et al. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature. 2015;525:389–93.PubMedPubMedCentralCrossRef Zhang Q, Zhao K, Shen Q, Han Y, Gu Y, Li X, et al. Tet2 is required to resolve inflammation by recruiting Hdac2 to specifically repress IL-6. Nature. 2015;525:389–93.PubMedPubMedCentralCrossRef
18.
go back to reference Cull AH, Snetsinger B, Buckstein R, Wells RA, Rauh MJ. Tet2 restrains inflammatory gene expression in macrophages. Exp Hematol. 2017;55:56–7.PubMedCrossRef Cull AH, Snetsinger B, Buckstein R, Wells RA, Rauh MJ. Tet2 restrains inflammatory gene expression in macrophages. Exp Hematol. 2017;55:56–7.PubMedCrossRef
19.
go back to reference Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC, Chakraborty R, et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science. 2017;355:842–8.PubMedPubMedCentralCrossRef Fuster JJ, MacLauchlan S, Zuriaga MA, Polackal MN, Ostriker AC, Chakraborty R, et al. Clonal hematopoiesis associated with TET2 deficiency accelerates atherosclerosis development in mice. Science. 2017;355:842–8.PubMedPubMedCentralCrossRef
20.
go back to reference Deng W, Wang J, Zhang J, Cai J, Bai Z, Zhang Z. TET2 regulates LncRNA-ANRIL expression and inhibits the growth of human gastric cancer cells. IUBMB Life. 2016;68:355–63.PubMedCrossRef Deng W, Wang J, Zhang J, Cai J, Bai Z, Zhang Z. TET2 regulates LncRNA-ANRIL expression and inhibits the growth of human gastric cancer cells. IUBMB Life. 2016;68:355–63.PubMedCrossRef
21.
go back to reference Nickerson ML, Das S, Im KM, Turan S, Berndt SI, Li H, et al. TET2 binds the androgen receptor and loss is associated with prostate cancer. Oncogene. 2017;36:2172–82.PubMedCrossRef Nickerson ML, Das S, Im KM, Turan S, Berndt SI, Li H, et al. TET2 binds the androgen receptor and loss is associated with prostate cancer. Oncogene. 2017;36:2172–82.PubMedCrossRef
22.
go back to reference Alrehaili AA, Gharib AF, Alghamdi SA, Alhazmi A, Al-Shehri SS, Hagag HM, et al. Evaluation of TET family gene expression and 5-hydroxymethylcytosine as potential epigenetic markers in non-small cell lung cancer. In Vivo. 2023;37:445–54.PubMedPubMedCentralCrossRef Alrehaili AA, Gharib AF, Alghamdi SA, Alhazmi A, Al-Shehri SS, Hagag HM, et al. Evaluation of TET family gene expression and 5-hydroxymethylcytosine as potential epigenetic markers in non-small cell lung cancer. In Vivo. 2023;37:445–54.PubMedPubMedCentralCrossRef
23.
go back to reference Lyu R, Zhu X, Shen Y, Xiong L, Liu L, Liu H, et al. Tumour suppressor TET2 safeguards enhancers from aberrant DNA methylation and epigenetic reprogramming in ERα-positive breast cancer cells. Epigenetics. 2022;17:1180–1.PubMedCrossRef Lyu R, Zhu X, Shen Y, Xiong L, Liu L, Liu H, et al. Tumour suppressor TET2 safeguards enhancers from aberrant DNA methylation and epigenetic reprogramming in ERα-positive breast cancer cells. Epigenetics. 2022;17:1180–1.PubMedCrossRef
24.
go back to reference Lopez-Bertoni H, Johnson A, Rui Y, Lal B, Sall S, Malloy M, et al. Sox2 induces glioblastoma cell stemness and tumor propagation by repressing TET2 and deregulating 5hmC and 5mC DNA modifications. Signal Transduct Target Ther. 2022;7:37.PubMedPubMedCentralCrossRef Lopez-Bertoni H, Johnson A, Rui Y, Lal B, Sall S, Malloy M, et al. Sox2 induces glioblastoma cell stemness and tumor propagation by repressing TET2 and deregulating 5hmC and 5mC DNA modifications. Signal Transduct Target Ther. 2022;7:37.PubMedPubMedCentralCrossRef
25.
go back to reference Gong F, Guo Y, Niu Y, Jin J, Zhang X, Shi X, et al. Epigenetic silencing of TET2 and TET3 induces an EMT-like process in melanoma. Oncotarget. 2017;8:315–23.PubMedCrossRef Gong F, Guo Y, Niu Y, Jin J, Zhang X, Shi X, et al. Epigenetic silencing of TET2 and TET3 induces an EMT-like process in melanoma. Oncotarget. 2017;8:315–23.PubMedCrossRef
26.
go back to reference Adhikari BR, Uehara O, Matsuoka H, Takai R, Harada F, Utsunomiya M, et al. Immunohistochemical evaluation of Klotho and DNA methyltransferase 3a in oral squamous cell carcinomas. Med Mol Morphol. 2017;50:155–61.PubMedCrossRef Adhikari BR, Uehara O, Matsuoka H, Takai R, Harada F, Utsunomiya M, et al. Immunohistochemical evaluation of Klotho and DNA methyltransferase 3a in oral squamous cell carcinomas. Med Mol Morphol. 2017;50:155–61.PubMedCrossRef
27.
go back to reference Yakushiji T, Uzawa K, Shibahara T, Noma H, Tanzawa H. Over-expression of DNA methyltransferases and CDKN2A gene methylation status in squamous cell carcinoma of the oral cavity. Int J Oncol. 2003;22:1201–11.PubMed Yakushiji T, Uzawa K, Shibahara T, Noma H, Tanzawa H. Over-expression of DNA methyltransferases and CDKN2A gene methylation status in squamous cell carcinoma of the oral cavity. Int J Oncol. 2003;22:1201–11.PubMed
28.
go back to reference Daniel FI, Rivero ER, Modolo F, Lopes TG, Salum FG. Immunohistochemical expression of DNA methyltransferases 1, 3a and 3b in oral leukoplakias and squamous cell carcinomas. Arch Oral Biol. 2010;55:1024–31.PubMedCrossRef Daniel FI, Rivero ER, Modolo F, Lopes TG, Salum FG. Immunohistochemical expression of DNA methyltransferases 1, 3a and 3b in oral leukoplakias and squamous cell carcinomas. Arch Oral Biol. 2010;55:1024–31.PubMedCrossRef
29.
go back to reference Supic G, Kozomara R, Zeljic K, Jovic N, Magic Z. Prognostic value of the DNMTs mRNA expression and genetic polymorphisms on the clinical outcome in oral cancer patients. Clin Oral Invest. 2017;21:173–81.CrossRef Supic G, Kozomara R, Zeljic K, Jovic N, Magic Z. Prognostic value of the DNMTs mRNA expression and genetic polymorphisms on the clinical outcome in oral cancer patients. Clin Oral Invest. 2017;21:173–81.CrossRef
30.
go back to reference Jäwert F, Hasséus B, Kjeller G, Magnusson B, Sand L, Larsson L. Loss of 5-hydroxymethylcytosine and TET2 in oral squamous cell carcinoma. Anticancer Res. 2013;33:4325–34.PubMed Jäwert F, Hasséus B, Kjeller G, Magnusson B, Sand L, Larsson L. Loss of 5-hydroxymethylcytosine and TET2 in oral squamous cell carcinoma. Anticancer Res. 2013;33:4325–34.PubMed
31.
go back to reference Wang X, Zhang Y, Sun L, Wang S, Nie J, Zhao W, et al. Evaluation of the clinical application of multiple tumor marker protein chip in the diagnostic of lung cancer. J Clin Lab Anal. 2018;32:e22565.PubMedPubMedCentralCrossRef Wang X, Zhang Y, Sun L, Wang S, Nie J, Zhao W, et al. Evaluation of the clinical application of multiple tumor marker protein chip in the diagnostic of lung cancer. J Clin Lab Anal. 2018;32:e22565.PubMedPubMedCentralCrossRef
33.
go back to reference Yu J, Ge Z, Chen S, Li S, Zhang X, Hu J, et al. miR-26a-5p suppresses Wnt/β-catenin signaling pathway by inhibiting DNMT3A-mediated SFRP1 methylation and inhibits cancer stem cell-like properties of NSCLC. Dis Markers. 2022;2022:7926483.PubMedPubMedCentralCrossRef Yu J, Ge Z, Chen S, Li S, Zhang X, Hu J, et al. miR-26a-5p suppresses Wnt/β-catenin signaling pathway by inhibiting DNMT3A-mediated SFRP1 methylation and inhibits cancer stem cell-like properties of NSCLC. Dis Markers. 2022;2022:7926483.PubMedPubMedCentralCrossRef
35.
go back to reference Pang Y, Liu J, Li X, Xiao G, Wang H, Yang G, et al. MYC and DNMT3A-mediated DNA methylation represses microRNA-200b in triple negative breast cancer. J Cell Mol Med. 2018;22:6262–6.PubMedPubMedCentralCrossRef Pang Y, Liu J, Li X, Xiao G, Wang H, Yang G, et al. MYC and DNMT3A-mediated DNA methylation represses microRNA-200b in triple negative breast cancer. J Cell Mol Med. 2018;22:6262–6.PubMedPubMedCentralCrossRef
36.
go back to reference Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene. 2002;21:5427–35.PubMedCrossRef Esteller M. CpG island hypermethylation and tumor suppressor genes: a booming present, a brighter future. Oncogene. 2002;21:5427–35.PubMedCrossRef
37.
go back to reference Hitchins MP, Ward RL. Constitutional (germline) MLH1 epimutation as an aetiological mechanism for hereditary non-polyposis colorectal cancer. J Med Genet. 2009;46:793–8.PubMedCrossRef Hitchins MP, Ward RL. Constitutional (germline) MLH1 epimutation as an aetiological mechanism for hereditary non-polyposis colorectal cancer. J Med Genet. 2009;46:793–8.PubMedCrossRef
38.
go back to reference Casalino L, Verde P. Multifaceted roles of DNA methylation in neoplastic transformation, from tumor suppressors to EMT and metastasis. Genes. 2020;11:922.PubMedPubMedCentralCrossRef Casalino L, Verde P. Multifaceted roles of DNA methylation in neoplastic transformation, from tumor suppressors to EMT and metastasis. Genes. 2020;11:922.PubMedPubMedCentralCrossRef
39.
go back to reference Markou Α, Londra D, Tserpeli V, Kollias Ι, Tsaroucha E, Vamvakaris I, et al. DNA methylation analysis of tumor suppressor genes in liquid biopsy components of early stage NSCLC: a promising tool for early detection. Clin Epigenet. 2022;14:61.CrossRef Markou Α, Londra D, Tserpeli V, Kollias Ι, Tsaroucha E, Vamvakaris I, et al. DNA methylation analysis of tumor suppressor genes in liquid biopsy components of early stage NSCLC: a promising tool for early detection. Clin Epigenet. 2022;14:61.CrossRef
41.
go back to reference Lian H, Li WB, Jin WL. The emerging insights into catalytic or non-catalytic roles of TET proteins in tumors and neural development. Oncotarget. 2016;7:64512–6.PubMedPubMedCentralCrossRef Lian H, Li WB, Jin WL. The emerging insights into catalytic or non-catalytic roles of TET proteins in tumors and neural development. Oncotarget. 2016;7:64512–6.PubMedPubMedCentralCrossRef
43.
go back to reference El-Harakeh M, Saliba J, SharafAldeen K, Haidar M, El Hajjar L, Awad MK, et al. Expression of the methylcytosine dioxygenase ten-eleven translocation-2 and connexin 43 in inflammatory bowel disease and colorectal cancer. World J Gastroenterol. 2022;28:5845–55.PubMedPubMedCentralCrossRef El-Harakeh M, Saliba J, SharafAldeen K, Haidar M, El Hajjar L, Awad MK, et al. Expression of the methylcytosine dioxygenase ten-eleven translocation-2 and connexin 43 in inflammatory bowel disease and colorectal cancer. World J Gastroenterol. 2022;28:5845–55.PubMedPubMedCentralCrossRef
44.
go back to reference Gao J, Liu R, Feng D, Huang W, Huo M, Zhang J, et al. Snail/PRMT5/NuRD complex contributes to DNA hypermethylation in cervical cancer by TET1 inhibition. Cell Death Differ. 2021;28:2818–22.PubMedPubMedCentralCrossRef Gao J, Liu R, Feng D, Huang W, Huo M, Zhang J, et al. Snail/PRMT5/NuRD complex contributes to DNA hypermethylation in cervical cancer by TET1 inhibition. Cell Death Differ. 2021;28:2818–22.PubMedPubMedCentralCrossRef
45.
go back to reference Fujikura K, Alruwaii ZI, Haffner MC, Trujillo MA, Roberts NJ, Hong SM, et al. Downregulation of 5-hydroxymethylcytosine is an early event in pancreatic tumorigenesis. J Pathol. 2021;254:279–82.PubMedPubMedCentralCrossRef Fujikura K, Alruwaii ZI, Haffner MC, Trujillo MA, Roberts NJ, Hong SM, et al. Downregulation of 5-hydroxymethylcytosine is an early event in pancreatic tumorigenesis. J Pathol. 2021;254:279–82.PubMedPubMedCentralCrossRef
Metadata
Title
Correlation of DNA methylation of DNMT3A and TET2 with oral squamous cell carcinoma
Authors
Xueming Li
Zaikun Li
Qingxi Gao
Yanan Peng
Yang Yu
Tenglong Hu
Wei Wang
Publication date
01-12-2024
Publisher
Springer US
Published in
Discover Oncology / Issue 1/2024
Print ISSN: 1868-8497
Electronic ISSN: 2730-6011
DOI
https://doi.org/10.1007/s12672-024-00866-9

Other articles of this Issue 1/2024

Discover Oncology 1/2024 Go to the issue
Live Webinar | 27-06-2024 | 18:00 (CEST)

Keynote webinar | Spotlight on medication adherence

Live: Thursday 27th June 2024, 18:00-19:30 (CEST)

WHO estimates that half of all patients worldwide are non-adherent to their prescribed medication. The consequences of poor adherence can be catastrophic, on both the individual and population level.

Join our expert panel to discover why you need to understand the drivers of non-adherence in your patients, and how you can optimize medication adherence in your clinics to drastically improve patient outcomes.

Prof. Kevin Dolgin
Prof. Florian Limbourg
Prof. Anoop Chauhan
Developed by: Springer Medicine
Obesity Clinical Trial Summary

At a glance: The STEP trials

A round-up of the STEP phase 3 clinical trials evaluating semaglutide for weight loss in people with overweight or obesity.

Developed by: Springer Medicine