Top

Cancer Cell International

Published in:

01-12-2020 | Cervical Cancer | Primary research

SUV39H1-DNMT3A-mediated epigenetic regulation of Tim-3 and galectin-9 in the cervical cancer

Authors: Li Zhang, Sijuan Tian, Minyi Zhao, Ting Yang, Shimin Quan, Qing Yang, Lihua Song, Xiaofeng Yang

Published in: Cancer Cell International | Issue 1/2020

Abstract

Background

Methylation of histone 3 at lysine 9 (H3K9) and DNA methylation are epigenetic marks correlated with genes silencing. The tumor microenvironment significantly influences therapeutic responses and clinical outcomes. The epigenetic-regulation mechanism of the costimulatory factors Tim-3 and galectin-9 in cervical cancer remains unknown.

Methods

The methylation status of HAVCR2 and LGALS9 were detected by MS-PCR in cervical cancer tissues and cell lines. The underlying molecular mechanism of SUV39H1-DNMT3A-Tim-3/galectin-9 regulation was elucidated using cervical cancer cell lines containing siRNA or/and over-expression system. Confirmation of the regulation of DNMT3A by SUV39H1 used ChIP-qPCR.

Results

SUV39H1 up-regulates H3K9me3 expression at the DNMT3A promoter region, which in turn induced expression of DNMT3A in cervical cancer. In addition, the mechanistic studies indicate that DNMT3A mediates the epigenetic modulation of the HAVCR2 and LGALS9 genes by directly binding to their promoter regions in vitro. Moreover, in an in vivo assay, the expression profile of SUV39H1 up-regulates the level of H3K9me3 at the DNMT3A promoter region was found to correlate with Tim-3 and galectin-9 cellular expression level.

Conclusion

These results indicate that SUV39H1-DNMT3A is a crucial Tim-3 and galectin-9 regulatory axis in cervical cancer.

Vu M, Yu J, Awolude OA, Chuang L. Cervical cancer worldwide. Curr Probl Cancer. 2018;42(5):457–65.PubMedCrossRef

Bray F, Ferlay J, Soerjomataram I, Siegel RL, Torre LA, Jemal A. Global cancer statistics 2018: GLOBOCAN estimates of incidence and mortality worldwide for 36 cancers in 185 countries. CA Cancer J Clin. 2018;68(6):394–424.PubMedCrossRef

Crosbie EJ, Einstein MH, Franceschi S, Kitchener HC. Human papillomavirus and cervical cancer. Lancet. 2013;382(9895):889–99.PubMedCrossRef

De Nola R, Menga A, Castegna A, Loizzi V, Ranieri G, Cicinelli E, Cormio G. The crowded crosstalk between cancer cells and stromal microenvironment in gynecological malignancies: biological pathways and therapeutic implication. Int J Mol Sci. 2019;20(10):2401.PubMedCentralCrossRef

Li X, Hu W, Zheng X, Zhang C, Du P, Zheng Z, Yang Y, Wu J, Ji M, Jiang J. Emerging immune checkpoints for cancer therapy. Acta Oncol. 2015;54(10):1706–13.PubMedCrossRef

Moriyama K, Kukita A, Li YJ, Uehara N, Zhang JQ, Takahashi I, Kukita T. Regulation of osteoclastogenesis through Tim-3: possible involvement of the Tim-3/galectin-9 system in the modulation of inflammatory bone destruction. Lab Invest. 2014;94(11):1200–11.PubMedCrossRef

Zhang H, Song Y, Yang H, Liu Z, Gao L, Liang X, Ma C. Tumor cell-intrinsic Tim-3 promotes liver cancer via NF-kappaB/IL-6/STAT3 axis. Oncogene. 2018;37(18):2456–68.PubMedCrossRef

Yan J, Zhang Y, Zhang JP, Liang J, Li L, Zheng L. Tim-3 expression defines regulatory T cells in human tumors. PLoS ONE. 2013;8(3):e58006.PubMedPubMedCentralCrossRef

Nowacka-Zawisza M, Wisnik E. DNA methylation and histone modifications as epigenetic regulation in prostate cancer (Review). Oncol Rep. 2017;38(5):2587–96.PubMedCrossRef

10.

Bhat S, Kabekkodu SP, Varghese VK, Chakrabarty S, Mallya SP, Rotti H, Pandey D, Kushtagi P, Satyamoorthy K. Aberrant gene-specific DNA methylation signature analysis in cervical cancer. Tumour Biol. 2017;39(3):1010428317694573.PubMedCrossRef

11.

Zhang L, Tian S, Pei M, Zhao M, Wang L, Jiang Y, Yang T, Zhao J, Song L, Yang X. Crosstalk between histone modification and DNA methylation orchestrates the epigenetic regulation of the costimulatory factors, Tim3 and galectin9, in cervical cancer. Oncol Rep. 2019;42(6):2655–69.PubMedPubMedCentral

12.

Du J, Johnson LM, Jacobsen SE, Patel DJ. DNA methylation pathways and their crosstalk with histone methylation. Nat Rev Mol Cell Biol. 2015;16(9):519–32.PubMedPubMedCentralCrossRef

13.

Lu C, Klement JD, Yang D, Albers T, Lebedyeva IO, Waller JL, Liu K. SUV39H1 regulates human colon carcinoma apoptosis and cell cycle to promote tumor growth. Cancer Lett. 2020;476:87–96.PubMedCrossRefPubMedCentral

14.

Lu C, Yang D, Klement JD, Oh IK, Savage NM, Waller JL, Colby AH, Grinstaff MW, Oberlies NH, Pearce CJ, et al. SUV39H1 represses the expression of cytotoxic T-lymphocyte effector genes to promote colon tumor immune evasion. Cancer Immunol Res. 2019;7(3):414–27.PubMedPubMedCentralCrossRef

15.

Wei X, Zhang S, Cao D, Zhao M, Zhang Q, Zhao J, Yang T, Pei M, Wang L, Li Y, et al. Aberrant hypermethylation of SALL3 with HPV involvement contributes to the carcinogenesis of cervical cancer. PLoS ONE. 2015;10(12):e0145700.PubMedPubMedCentralCrossRef

16.

Wang J, Yan W, Peng X, Jiang Y, He L, Peng Y, Chen X, Ye M, Zhuo H. Functional role of SUV39H1 in human renal tubular epithelial cells under high-glucose ambiance. Inflammation. 2018;41(1):1–10.PubMedCrossRef

17.

Shirai A, Kawaguchi T, Shimojo H, Muramatsu D, Ishida-Yonetani M, Nishimura Y, Kimura H, Nakayama JI, Shinkai Y. Impact of nucleic acid and methylated H3K9 binding activities of Suv39h1 on its heterochromatin assembly. eLife. 2017;6:e25317.PubMedPubMedCentralCrossRef

18.

Zhang S, Batur P. Human papillomavirus in 2019: an update on cervical cancer prevention and screening guidelines. Clevel Clin J Med. 2019;86(3):173–8.CrossRef

19.

Vidal E, Sayols S, Moran S, Guillaumet-Adkins A, Schroeder MP, Royo R, Orozco M, Gut M, Gut I, Lopez-Bigas N, et al. A DNA methylation map of human cancer at single base-pair resolution. Oncogene. 2017;36(40):5648–57.PubMedPubMedCentralCrossRef

20.

Xu W, Xu M, Wang L, Zhou W, Xiang R, Shi Y, Zhang Y, Piao Y. Integrative analysis of DNA methylation and gene expression identified cervical cancer-specific diagnostic biomarkers. Signal Transduct Target Ther. 2019;4:55.PubMedPubMedCentralCrossRef

21.

Schuyler RP, Merkel A, Raineri E, Altucci L, Vellenga E, Martens JHA, Pourfarzad F, Kuijpers TW, Burden F, Farrow S, et al. Distinct trends of DNA methylation patterning in the innate and adaptive immune systems. Cell Rep. 2016;17(8):2101–11.PubMedPubMedCentralCrossRef

22.

Ali MA, Matboli M, Tarek M, Reda M, Kamal KM, Nouh M, Ashry AM, El-Bab AF, Mesalam HA, Shafei AE, et al. Epigenetic regulation of immune checkpoints: another target for cancer immunotherapy? Immunotherapy. 2017;9(1):99–108.PubMedCrossRef

23.

Janson PC, Marits P, Thorn M, Ohlsson R, Winqvist O. CpG methylation of the IFNG gene as a mechanism to induce immunosuppression [correction of immunosupression] in tumor-infiltrating lymphocytes. J Immunol (Baltimore, Md: 1950). 2008;181(4):2878–86.CrossRef

24.

Cruz AF, de Resende RG, de Lacerda JCT, Pereira NB, Melo LA, Diniz MG, Gomes CC, Gomez RS. DNA methylation patterns of genes related to immune response in the different clinical forms of oral lichen planus. J Oral Pathol Med. 2018;47(1):91–5.PubMedCrossRef

25.

Ke X, Zhang S, Xu J, Liu G, Zhang L, Xie E, Gao L, Li D, Sun R, Wang F, et al. Non-small-cell lung cancer-induced immunosuppression by increased human regulatory T cells via Foxp3 promoter demethylation. Cancer Immunol Immunother. 2016;65(5):587–99.PubMedCrossRef

26.

Vizoso M, Puig M, Carmona FJ, Maqueda M, Velasquez A, Gomez A, Labernadie A, Lugo R, Gabasa M, Rigat-Brugarolas LG, et al. Aberrant DNA methylation in non-small cell lung cancer-associated fibroblasts. Carcinogenesis. 2015;36(12):1453–63.PubMedPubMedCentral

27.

Kulis M, Esteller M. DNA methylation and cancer. Adv Genet. 2010;70:27–56.PubMedCrossRef

28.

Yang Y, Liu R, Qiu R, Zheng Y, Huang W, Hu H, Ji Q, He H, Shang Y, Gong Y, et al. CRL4B promotes tumorigenesis by coordinating with SUV39H1/HP1/DNMT3A in DNA methylation-based epigenetic silencing. Oncogene. 2015;34(1):104–18.PubMedCrossRef

29.

Ando M, Saito Y, Xu G, Bui NQ, Medetgul-Ernar K, Pu M, Fisch K, Ren S, Sakai A, Fukusumi T, et al. Chromatin dysregulation and DNA methylation at transcription start sites associated with transcriptional repression in cancers. Nat Commun. 2019;10(1):2188.PubMedPubMedCentralCrossRef

30.

Meldi KM, Gaconnet GA, Mayo KE. DNA methylation and histone modifications are associated with repression of the inhibin alpha promoter in the rat corpus luteum. Endocrinology. 2012;153(10):4905–17.PubMedPubMedCentralCrossRef

31.

Strunnikova M, Schagdarsurengin U, Kehlen A, Garbe JC, Stampfer MR, Dammann R. Chromatin inactivation precedes de novo DNA methylation during the progressive epigenetic silencing of the RASSF1A promoter. Mol Cell Biol. 2005;25(10):3923–33.PubMedPubMedCentralCrossRef

Title: SUV39H1-DNMT3A-mediated epigenetic regulation of Tim-3 and galectin-9 in the cervical cancer
Authors: Li Zhang
Sijuan Tian
Minyi Zhao
Ting Yang
Shimin Quan
Qing Yang
Lihua Song
Xiaofeng Yang
Publication date: 01-12-2020
Publisher: BioMed Central
Keywords: Cervical Cancer
Cervical Cancer
Epigenetics
Published in: Cancer Cell International / Issue 1/2020
Electronic ISSN: 1475-2867
DOI: https://doi.org/10.1186/s12935-020-01380-y

Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Watch now

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras

Prof. Fabrice Barlesi

Developed by: Springer Medicine

Keynote webinar | Spotlight on medication adherence

Springer Medicine

Abstract

Background

Methods

Results

Conclusion

Please log in to get access to this content

Other articles of this Issue 1/2020

Long non-coding RNA LINC01419 mediates miR-519a-3p/PDRG1 axis to promote cell progression in osteosarcoma

MicroRNA-19b-3p suppresses gastric cancer development by negatively regulating neuropilin-1

Expression profile analysis identifies key genes as prognostic markers for metastasis of osteosarcoma

Circ_002117 binds to microRNA-370 and promotes endoplasmic reticulum stress-induced apoptosis in gastric cancer

Establishment and characterization of breast cancer organoids from a patient with mammary Paget’s disease

LINC00152 upregulates ZEB1 expression and enhances epithelial-mesenchymal transition and oxaliplatin resistance in esophageal cancer by interacting with EZH2

Keynote webinar | Spotlight on antibody–drug conjugates in cancer