Skip to main content
Log in

SMYD2 facilitates cancer cell malignancy and xenograft tumor development through ERBB2-mediated FUT4 expression in colon cancer

  • Published:
Molecular and Cellular Biochemistry Aims and scope Submit manuscript

Abstract

The aim of this study is to assess the expression levels of SMYD2 in human tissue samples and cells of colon cancer, and further explore the potential mechanisms of SMYD2 in colon cancer progression. Quantitative PCR and Immunohistochemical (IHC) assays were performed to detect SMYD2 expression in 76 tissue samples of colon cancer tissues and the corresponding normal tissues. The potential correlations between SMYD2 expression levels and clinical pathological features were assessed. We further detected the effects of SMYD2 on the proliferation, invasion and apoptosis of colon cancer cells and on ERBB2/FUT4 signaling pathway through Brdu assay, transwell assay and flow cytometry assay, respectively. The potential effects of SMYD2 on tumor growth were explored using an animal model. We demonstrated the possible involvement of SMYD2 in the progression of colon cancer. We found the high expression of SMYD2 in human colon cancer tissues and cells, and found the correlations between SMYD2 expression and the clinicopathological features including vascular invasion (P = 0.007*), TNM stage (P = 0.016*) and lymph node metastasis (P = 0.011*), of patients with colon cancer. Our data further confirmed that SMYD2 affects cell proliferation, invasion, and apoptosis of colon cancer cells via the regulation of ERBB2/FUT4 signaling pathway. We also demonstrated SMYD2 contributed to tumor growth of colon cancer cells in vivo. We investigated the potential involvement of SMYD2 in the progression of colon, and therefore confirmed SMYD2 as a possible therapeutic target for colon cancer.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Fig. 1
Fig. 2
Fig. 3
Fig. 4
Fig. 5
Fig. 6

Similar content being viewed by others

Data availability

All data generated or analyzed during this study are included in this published article.

References

  1. Dewanji A, Jeon J, Meza R, Luebeck EG (2011) Number and size distribution of colorectal adenomas under the multistage clonal expansion model of cancer. PLoS Comput Biol 7(10):e1002213. https://doi.org/10.1371/journal.pcbi.1002213

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  2. Peng F, Huang Y, Li MY, Li GQ, Huang HC, Guan R, Chen ZC, Liang SP, Chen YH (2016) Dissecting characteristics and dynamics of differentially expressed proteins during multistage carcinogenesis of human colorectal cancer. World J Gastroenterol 22(18):4515–4528. https://doi.org/10.3748/wjg.v22.i18.4515

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  3. Luebeck EG, Moolgavkar SH (2002) Multistage carcinogenesis and the incidence of colorectal cancer. Proc Natl Acad Sci USA 99(23):15095–15100. https://doi.org/10.1073/pnas.222118199

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  4. Abd-Elsatar AG, Farag MM, Youssef HF, Salih SA, Mounier MM, El-Meliegy E (2019) Different zeolite systems for colon cancer therapy: monitoring of ion release, cytotoxicity and drug release behavior. Prog Biomater 8(2):101–113. https://doi.org/10.1007/s40204-019-0115-8

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  5. Jahanafrooz Z, Mosafer J, Akbari M, Hashemzaei M, Mokhtarzadeh A, Baradaran B (2019) Colon cancer therapy by focusing on colon cancer stem cells and their tumor microenvironment. J Cell Physiol. https://doi.org/10.1002/jcp.29337

    Article  PubMed  Google Scholar 

  6. Zhao T, Feng Y, Guo M, Zhang C, Wu Q, Chen J, Guo S, Liu S, Zhou Q, Wang Z, Fan W, Zhang Y, Jia H, Feng Z (2019) Combination of attenuated Salmonella carrying PD-1 siRNA with nifuroxazide for colon cancer therapy. J Cell Biochem. https://doi.org/10.1002/jcb.29432

    Article  PubMed  PubMed Central  Google Scholar 

  7. Sajjad A, Novoyatleva T, Vergarajauregui S, Troidl C, Schermuly RT, Tucker HO (1843) Engel FB (2014) Lysine methyltransferase Smyd2 suppresses p53-dependent cardiomyocyte apoptosis. Biochem Biophys Acta 11:2556–2562. https://doi.org/10.1016/j.bbamcr.2014.06.019

    Article  CAS  Google Scholar 

  8. Sese B, Barrero MJ, Fabregat MC, Sander V, Izpisua Belmonte JC (2013) SMYD2 is induced during cell differentiation and participates in early development. Int J Dev Biol 57(5):357–364. https://doi.org/10.1387/ijdb.130051ji

    Article  CAS  PubMed  Google Scholar 

  9. Piao L, Kang D, Suzuki T, Masuda A, Dohmae N, Nakamura Y, Hamamoto R (2014) The histone methyltransferase SMYD2 methylates PARP1 and promotes poly(ADP-ribosyl)ation activity in cancer cells. Neoplasia 16(3):257–264. https://doi.org/10.1016/j.neo.2014.03.002

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  10. 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 (2015) Overexpression of SMYD2 contributes to malignant outcome in gastric cancer. Br J Cancer 112(2):357–364. https://doi.org/10.1038/bjc.2014.543

    Article  CAS  PubMed  Google Scholar 

  11. Hamamoto R, Toyokawa G, Nakakido M, Ueda K, Nakamura Y (2014) SMYD2-dependent HSP90 methylation promotes cancer cell proliferation by regulating the chaperone complex formation. Cancer Lett 351(1):126–133. https://doi.org/10.1016/j.canlet.2014.05.014

    Article  CAS  PubMed  Google Scholar 

  12. Reynoird N, Mazur PK, Stellfeld T, Flores NM, Lofgren SM, Carlson SM, Brambilla E, Hainaut P, Kaznowska EB, Arrowsmith CH, Khatri P, Stresemann C, Gozani O, Sage J (2016) Coordination of stress signals by the lysine methyltransferase SMYD2 promotes pancreatic cancer. Genes Dev 30(7):772–785. https://doi.org/10.1101/gad.275529.115

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  13. Bai HJ, Zhang P, Ma L, Liang H, Wei G, Yang HT (2019) SMYD2 Drives mesendodermal differentiation of human embryonic stem cells through mediating the transcriptional activation of key mesendodermal genes. Stem Cells 37(11):1401–1415. https://doi.org/10.1002/stem.3068

    Article  CAS  PubMed  Google Scholar 

  14. Wang R, Deng X, Yoshioka Y, Vougiouklakis T, Park JH, Suzuki T, Dohmae N, Ueda K, Hamamoto R, Nakamura Y (2017) Effects of SMYD2-mediated EML4-ALK methylation on the signaling pathway and growth in non-small-cell lung cancer cells. Cancer Sci 108(6):1203–1209. https://doi.org/10.1111/cas.13245

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  15. Munkanatta Godage DNP, VanHecke GC, Samarasinghe KTG, Feng HZ, Hiske M, Holcomb J, Yang Z, Jin JP, Chung CS, Ahn YH (2018) SMYD2 glutathionylation contributes to degradation of sarcomeric proteins. Nat Commun 9(1):4341. https://doi.org/10.1038/s41467-018-06786-x

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  17. Galvan-Femenia I, Guindo M, Duran X, Calabuig-Farinas S, Mercader JM, Ramirez JL, Rosell R, Torrents D, Carreras A, Kohno T, Jantus-Lewintre E, Camps C, Perucho M, Sumoy L, Yokota J, de Cid R (2018) Genomic profiling in advanced stage non-small-cell lung cancer patients with platinum-based chemotherapy identifies germline variants with prognostic value in SMYD2. Cancer Treat Res Commun 15:21–31. https://doi.org/10.1016/j.ctarc.2018.02.003

    Article  PubMed  Google Scholar 

  18. Zuo SR, Zuo XC, He Y, Fang WJ, Wang CJ, Zou H, Chen P, Huang LF, Huang LH, Xiang H, Liu SK (2018) Positive expression of SMYD2 is associated with poor prognosis in patients with primary hepatocellular carcinoma. J Cancer 9(2):321–330. https://doi.org/10.7150/jca.22218

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  19. Sakamoto LH, Andrade RV, Felipe MS, Motoyama AB, Pittella Silva F (2014) SMYD2 is highly expressed in pediatric acute lymphoblastic leukemia and constitutes a bad prognostic factor. Leuk Res 38(4):496–502. https://doi.org/10.1016/j.leukres.2014.01.013

    Article  CAS  PubMed  Google Scholar 

  20. Zipin-Roitman A, Aqaqe N, Yassin M, Biechonski S, Amar M, van Delft MF, Gan OI, McDermott SP, Buzina A, Ketela T, Shlush L, Xie S, Voisin V, Moffat J, Minden MD, Dick JE, Milyavsky M (2017) SMYD2 lysine methyltransferase regulates leukemia cell growth and regeneration after genotoxic stress. Oncotarget 8(10):16712–16727. https://doi.org/10.18632/oncotarget.15147

    Article  PubMed  PubMed Central  Google Scholar 

  21. Hamaguchi J, Nakagawa H, Takahashi M, Kudo T, Kamiyama N, Sun B, Oshima T, Sato Y, Deguchi K, Todo S, Nishimura S (2007) Swainsonine reduces 5-fluorouracil tolerance in the multistage resistance of colorectal cancer cell lines. Mol Cancer 6:58. https://doi.org/10.1186/1476-4598-6-58

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  22. Troiani T, Napolitano S, Della Corte CM, Martini G, Martinelli E, Morgillo F, Ciardiello F (2016) Therapeutic value of EGFR inhibition in CRC and NSCLC: 15 years of clinical evidence. ESMO open 1(5):e000088. https://doi.org/10.1136/esmoopen-2016-000088

    Article  PubMed  PubMed Central  Google Scholar 

  23. Sobral RA, Honda ST, Katayama ML, Brentani H, Brentani MM, Patrao DF, Folgueira MA (2008) Tumor slices as a model to evaluate doxorubicin in vitro treatment and expression of trios of genes PRSS11, MTSS1, CLPTM1 and PRSS11, MTSS1, SMYD2 in canine mammary gland cancer. Acta Vet Scand 50:27. https://doi.org/10.1186/1751-0147-50-27

    Article  CAS  PubMed  PubMed Central  Google Scholar 

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

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  25. Thomenius MJ, Totman J, Harvey D, Mitchell LH, Riera TV, Cosmopoulos K, Grassian AR, Klaus C, Foley M, Admirand EA, Jahic H, Majer C, Wigle T, Jacques SL, Gureasko J, Brach D, Lingaraj T, West K, Smith S, Rioux N, Waters NJ, Tang C, Raimondi A, Munchhof M, Mills JE, Ribich S, Porter Scott M, Kuntz KW, Janzen WP, Moyer M, Smith JJ, Chesworth R, Copeland RA, Boriack-Sjodin PA (2018) Small molecule inhibitors and CRISPR/Cas9 mutagenesis demonstrate that SMYD2 and SMYD3 activity are dispensable for autonomous cancer cell proliferation. PLoS ONE 13(6):e0197372. https://doi.org/10.1371/journal.pone.0197372

    Article  CAS  PubMed  PubMed Central  Google Scholar 

  26. Ren H, Wang Z, Chen Y, Liu Y, Zhang S, Zhang T, Li Y (2019) SMYD2-OE promotes oxaliplatin resistance in colon cancer through MDR1/P-glycoprotein via MEK/ERK/AP1 pathway. OncoTargets Ther 12:2585–2594. https://doi.org/10.2147/OTT.S186806

    Article  CAS  Google Scholar 

Download references

Funding

Not applicable.

Author information

Authors and Affiliations

Authors

Contributions

YY conceived and designed the experiments, YZL analyzed and interpreted the results of the experiments, and YZL and YY performed the experiments.

Corresponding author

Correspondence to Yang Yang.

Ethics declarations

Conflict of interest

The authors state that there are no conflicts of interest to disclose.

Ethical approval

Tumor tissues were obtained from Chongqing University Cancer Hospital. All procedures performed in studies involving human participants were in accordance with the standards upheld by the Ethics Committee of Chongqing University Cancer Hospital and with those of the 1964 Helsinki Declaration and its later amendments for ethical research involving human subjects. All animal assay processes were approved by the Ethics Committee of Chongqing University for the use of animals and conducted in accordance with the National Institutes of Health Laboratory Animal Care and Use Guidelines.

Additional information

Publisher's Note

Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Rights and permissions

Reprints and permissions

About this article

Check for updates. Verify currency and authenticity via CrossMark

Cite this article

Lai, Y., Yang, Y. SMYD2 facilitates cancer cell malignancy and xenograft tumor development through ERBB2-mediated FUT4 expression in colon cancer. Mol Cell Biochem 477, 2149–2159 (2022). https://doi.org/10.1007/s11010-020-03738-2

Download citation

  • Received:

  • Accepted:

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s11010-020-03738-2

Keywords

Navigation