SET and MYND domain-containing protein 2 (SMYD2): a prognostic biomarker associated with immune infiltrates in cervical squamous cell carcinoma and endocervical adenocarcinoma

Authors

DOI:

https://doi.org/10.2298/ABS220413014A

Keywords:

cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC), SMYD2, immune infiltration

Abstract

Paper description:

  • Cervical cancers are diagnosed at an advanced stage. There is an urgent need to identify a biomarker to predict prognosis.
  • We examined the prognostic value and expression level of SMYD2 in cervical cancer and explored the exact mechanism by SMYD2 knockdown in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) cells.
  • SMYD2 promotes cell growth and migration. High SMYD2 expression in the cervical cancer microenvironment is linked to poor prognosis and tumor-infiltrating immune cells.
  • SMYD2 is a potential predictive biomarker that could serve as a promising molecular therapeutic target for cervical cancer.

Abstract: The histone lysine methyltransferase SET (Suppressor of variegation, Enhancer of Zeste, Trithorax) and MYND (Myeloid-Nervy-DEAF1) domain-containing protein (SMYD2) plays a role in the tumorigenesis of cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC). However, the prognostic significance of SMYD2 in CESC and the link between SMYD2 and tumor-infiltrating immune cells are unknown. The prognostic value of SMYD2 in CESC was obtained from The Cancer Genome Atlas (TCGA). SMYD2 mRNA and protein were both highly expressed in CESC compared with normal tissues. The high expression of SMYD2 was associated with advanced tumor status and poor prognosis in CESC patients. SMYD2 was an independent prognostic factor for overall survival. In vitro experiments with knockdown of SMYD2 suppressed CESC cell migration and invasion. The online tumor immune estimation resource (TIMER) and Kaplan-Meier analysis results revealed that the infiltration of CD4+ T and CD8+ T cells was related to poor prognosis. In TIMER-based multivariate Cox regression analysis, CD8+ T cells and SMYD2 were demonstrated as independent prognostic factors of CESC. In conclusion, our data suggest that high SMYD2 expression is a predictor of poor prognosis in CESC patients; SMYD2 could serve as a prognostic biomarker and molecular therapeutic target for CESC.

Downloads

Download data is not yet available.

References

Friedman CF, Snyder Charen A, Zhou Q, Carducci MA, Buckley De Meritens A, Corr BR, Fu S, Hollmann TJ, Iasonos A, Konner JA, Konstantinopoulos PA, Modesitt SC, Sharon E, Aghajanian C, Zamarin D. Phase II study of atezolizumab in combination with bevacizumab in patients with advanced cervical cancer. J Immunother Cancer. 2020;8(2):e001126. https://doi.org/10.1136/jitc-2020-001126

Ding H, Xiong XX, Fan GL, Yi YX, Chen YR, Wang JT, Zhang W. The New Biomarker for Cervical Squamous Cell Carcinoma and Endocervical Adenocarcinoma (CESC) Based on Public Database Mining. BioMed Res Int. 2020;2020:5478574. https://doi.org/10.1155/2020/5478574

Brown MA, Sims RJ, 3rd, Gottlieb PD, Tucker PW. Identification and characterization of Smyd2: a split SET/MYND domain-containing histone H3 lysine 36-specific methyltransferase that interacts with the Sin3 histone deacetylase complex. Mol Cancer. 2006;5:26. https://doi.org/10.1186/1476-4598-5-26

Abu-Farha M, Lambert JP, Al-Madhoun AS, Elisma F, Skerjanc IS, Figeys D. The tale of two domains: proteomics and genomics analysis of SMYD2, a new histone methyltransferase. Mol Cell Proteomics. 2008;7(3):560-72. https://doi.org/10.1074/mcp.M700271-MCP200

Yi X, Jiang XJ, Fang ZM. Histone methyltransferase SMYD2: ubiquitous regulator of disease. Clin Epigenetics. 2019;11(1):112. https://doi.org/10.1186/s13148-019-0711-4

Komatsu S, Ichikawa D, Hirajima S, Nagata H, Nishimura Y, Kawaguchi T, Miyamae M, Okajima W, Ohashi T, Konishi H, Shiozaki A, Fujiwara H, Okamoto K, Tsuda H, Imoto I, Inazawa J, Otsuji E. Overexpression of SMYD2 contributes to malignant outcome in gastric cancer. Br J Cancer. 2015;112(2):357-64. https://doi.org/10.1038/bjc.2014.543

Li LX, Zhou JX, Calvet JP, Godwin AK, Jensen RA, Li X. Lysine methyltransferase SMYD2 promotes triple negative breast cancer progression. Cell Death Dis. 2018;9(3):326. https://doi.org/10.1038/s41419-018-0347-x

Meng F, Liu X, Lin C, Xu L, Liu J, Zhang P, Zhang X, Song J, Yan Y, Ren Z, Zhang Y. SMYD2 suppresses APC2 expression to activate the Wnt/β-catenin pathway and promotes epithelial-mesenchymal transition in colorectal cancer. Am J Cancer Res. 2020;10(3):997-1011.

Sun JJ, Li HL, Ma H, Shi Y, Yin LR, Guo SJ. SMYD2 promotes cervical cancer growth by stimulating cell proliferation. Cell Biosci. 2019;9:75. https://doi.org/10.1186/s13578-019-0340-9

Tang Z, Li C, Kang B, Gao G, Li C, Zhang Z. GEPIA: a web server for cancer and normal gene expression profiling and interactive analyses. Nucleic Acids Res. 2017;45(W1):W98-102. https://doi.org/10.1093/nar/gkx247

Li T, Fan J, Wang B, Traugh N, Chen Q, Liu JS, Li B, Liu XS. TIMER: A Web Server for Comprehensive Analysis of Tumor-Infiltrating Immune Cells. Cancer Res. 2017;77(21):e108-10. https://doi.org/10.1158/0008-5472.CAN-17-0307

Hamamoto R, Toyokawa G, Nakakido M, Ueda K, Nakamura Y. SMYD2-dependent HSP90 methylation promotes cancer cell proliferation by regulating the chaperone complex formation. Cancer Lett. 2014;351(1):126-33. https://doi.org/10.1016/j.canlet.2014.05.014

Wu L, Kou F, Ji Z, Li B, Zhang B, Guo Y, Yang L. SMYD2 promotes tumorigenesis and metastasis of lung adenocarcinoma through RPS7. Cell Death Dis. 2021;12(5):439. https://doi.org/10.1038/s41419-021-03720-w

Zuo SR, Zuo XC, He Y, Fang WJ, Wang CJ, Zou H, Chen P, Huang LF, Huang LH, Xiang H, Liu SK. Positive Expression of SMYD2 is Associated with Poor Prognosis in Patients with Primary Hepatocellular Carcinoma. J Cancer. 2018;9(2):321-30. https://doi.org/10.7150/jca.22218

Revathidevi S, Munirajan AK. Akt in cancer: Mediator and more. Semin Cancer Biol. 2019;59:80-91. https://doi.org/10.1016/j.semcancer.2019.06.002

González-Magaña A, Blanco FJ. Human PCNA Structure, Function and Interactions. Biomolecules. 2020;10(4). https://doi.org/10.3390/biom10040570

Wang Y, Jin G, Guo Y, Cao Y, Niu S, Fan X, Zhang J. SMYD2 suppresses p53 activity to promote glucose metabolism in cervical cancer. Exp Cell Res. 2021;404(2):112649. https://doi.org/10.1016/j.yexcr.2021.112649

Yu YQ, Thonn V, Patankar JV, Thoma OM, Waldner M, Zielinska M, Bao LL, Gonzalez-Acera M, Wallmüller S, Engel FB, Stürzl M, Neurath MF, Liebing E, Becker C. SMYD2 targets RIPK1 and restricts TNF-induced apoptosis and necroptosis to support colon tumor growth. Cell Death Dis. 2022;13(1):52. https://doi.org/10.1038/s41419-021-04483-0

Lee P, Chandel NS, Simon MC. Cellular adaptation to hypoxia through hypoxia inducible factors and beyond. Nat Rev Mol Cell Biol. 2020;21(5):268-83. https://doi.org/10.1038/s41580-020-0227-y

Evan GI, Vousden KH. Proliferation, cell cycle and apoptosis in cancer. Nature. 2001;411(6835):342-8. https://doi.org/10.1038/35077213

Eifler K, Vertegaal ACO. SUMOylation-Mediated Regulation of Cell Cycle Progression and Cancer. Trends Biochem Sci. 2015;40(12):779-93. https://doi.org/10.1016/j.tibs.2015.09.006

Baretti M, Le DT. DNA mismatch repair in cancer. Pharmacol Ther. 2018;189:45-62. https://doi.org/10.1016/j.pharmthera.2018.04.004

Wu X, Peng L, Zhang Y, Chen S, Lei Q, Li G, Zhang C. Identification of Key Genes and Pathways in Cervical Cancer by Bioinformatics Analysis. Int J Med Sci. 2019;16(6):800-12. https://doi.org/10.7150/ijms.34172

Bywater MJ, Pearson RB, McArthur GA, Hannan RD. Dysregulation of the basal RNA polymerase transcription apparatus in cancer. Nature reviews Cancer. 2013;13(5):299-314. https://doi.org/10.1038/nrc3496

Tian Y, Sun F, Zhong Y, Huang W, Wang G, Liu C, Xiao Y, Wu J, Mu L. Expression and Clinical Significance of POLR1D in Colorectal Cancer. Oncology. 2020;98(3):138-45. https://doi.org/10.1159/000504174

Noordhuis MG, Fehrmann RS, Wisman GB, Nijhuis ER, van Zanden JJ, Moerland PD, Ver Loren van Themaat E, Volders HH, Kok M, ten Hoor KA, Hollema H, de Vries EG, de Bock GH, van der Zee AG, Schuuring E. Involvement of the TGF-beta and beta-catenin pathways in pelvic lymph node metastasis in early-stage cervical cancer. Clin Cancer Res. 2011;17(6):1317-30. https://doi.org/10.1158/1078-0432.CCR-10-2320

Chen J, Deng Y, Ao L, Song Y, Xu Y, Wang CC, Choy KW, Tony Chung KH, Du Q, Sui Y, Yang T, Yang J, Li H, Zou C, Tang T. The high-risk HPV oncogene E7 upregulates miR-182 expression through the TGF-β/Smad pathway in cervical cancer. Cancer letters. 2019;460:75-85. https://doi.org/10.1016/j.canlet.2019.06.015

Yuan J, Yi K, Yang L. TGFBR2 Regulates Hedgehog Pathway and Cervical Cancer Cell Proliferation and Migration by Mediating SMAD4. J Proteome Res. 2020;19(8):3377-85. https://doi.org/10.1021/acs.jproteome.0c00239

Lee SY, Kwon J, Woo JH, Kim KH, Lee KA. Bcl2l10 mediates the proliferation, invasion and migration of ovarian cancer cells. Int J Oncol. 2020;56(2):618-29. https://doi.org/10.3892/ijo.2019.4949

Yarla NS, Bishayee A, Sethi G, Reddanna P, Kalle AM, Dhananjaya BL, Dowluru KS, Chintala R, Duddukuri GR. Targeting arachidonic acid pathway by natural products for cancer prevention and therapy. Semin Cancer Biol. 2016;40-41:48-81. https://doi.org/10.1016/j.semcancer.2016.02.001

Drake JM, Strohbehn G, Bair TB, Moreland JG, Henry MD. ZEB1 enhances transendothelial migration and represses the epithelial phenotype of prostate cancer cells. Mol Biol Cell. 2009;20(8):2207-17. https://doi.org/10.1091/mbc.e08-10-1076

Fridman WH, Pagès F, Sautès-Fridman C, Galon J. The immune contexture in human tumours: impact on clinical outcome. Nat Rev Cancer. 2012;12(4):298-306. https://doi.org/10.1038/nrc3245

He QF, Xu Y, Li J, Huang ZM, Li XH, Wang X. CD8+ T-cell exhaustion in cancer: mechanisms and new area for cancer immunotherapy. Brief Funct Genomics. 2019;18(2):99-106. https://doi.org/10.1093/bfgp/ely006

Chen J, Wang Z, Wang W, Ren S, Xue J, Zhong L, Jiang T, Wei H, Zhang C. SYT16 is a prognostic biomarker and correlated with immune infiltrates in glioma: A study based on TCGA data. Int Immunopharmacol. 2020;84:106490. https://doi.org/10.1016/j.intimp.2020.106490

Mami-Chouaib F, Blanc C, Corgnac S, Hans S, Malenica I, Granier C, Tihy I, Tartour E. Resident memory T cells, critical components in tumor immunology. J Immunother Cancer. 2018;6(1):87. https://doi.org/10.1186/s40425-018-0399-6

Jiang X, Xu J, Liu M, Xing H, Wang Z, Huang L, Mellor AL, Wang W, Wu S. Adoptive CD8(+) T cell therapy against cancer:Challenges and opportunities. Cancer Lett. 2019;462:23-32. https://doi.org/10.1016/j.canlet.2019.07.017

Xu F, Guan Y, Xue L, Huang S, Gao K, Yang Z, Chong T. The effect of a novel glycolysis-related gene signature on progression, prognosis and immune microenvironment of renal cell carcinoma. BMC Cancer. 2020;20(1):1207. https://doi.org/10.1186/s12885-020-07702-7

Downloads

Published

2022-06-27

How to Cite

1.
An Z, Cai D, Lin X, Xu S, Bin J, Jin X. SET and MYND domain-containing protein 2 (SMYD2): a prognostic biomarker associated with immune infiltrates in cervical squamous cell carcinoma and endocervical adenocarcinoma. Arch Biol Sci [Internet]. 2022Jun.27 [cited 2024Mar.28];74(2):147-58. Available from: https://serbiosoc.org.rs/arch/index.php/abs/article/view/7661

Issue

Section

Articles

Most read articles by the same author(s)