Open Access

EZH2 and SMYD3 expression in papillary thyroid cancer

  • Authors:
    • Nadia Sawicka‑Gutaj
    • Sara Shawkat
    • Mirosław Andrusiewicz
    • Paulina Ziółkowska
    • Agata Czarnywojtek
    • Paweł Gut
    • Marek Ruchała
  • View Affiliations

  • Published online on: March 2, 2021     https://doi.org/10.3892/ol.2021.12603
  • Article Number: 342
  • Copyright: © Sawicka‑Gutaj et al. This is an open access article distributed under the terms of Creative Commons Attribution License.

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Abstract

Recent studies have revealed the significant role of SMYD3 and EZH2 genes in the development and aggressiveness of numerous types of malignant tumor. Therefore, the present study aimed to investigate the expression of SMYD3 and EZH2 in papillary thyroid cancer, and to determine the correlation between the expression of these genes and clinical characteristics. Resected thyroid tissue samples from 62 patients with papillary thyroid cancer were investigated. Thyroid tissue derived from the healthy regions of removed nodular goiters from 30 patients served as the control group. Reverse transcription‑quantitative PCR analysis was employed to detect relative mRNA expression levels. Primer sequences and TaqMan® hydrolysis probe positions for EZH2 and SMYD3 were determined using the Roche Universal ProbeLibrary Assay Design Center version 2.50. EZH2 expression was detected in all thyroid cancer samples and in 83.3% of benign lesions. Notably, EZH2 was revealed to be upregulated in thyroid cancer tissues compared with control tissues (P=0.0002). EZH2 expression was positively correlated with tumor stage (P<0.0001; r=0.504), and multiple comparison analysis revealed that the highest expression of EZH2 was detected in samples staged pT4 (P=0.0001). SMYD3 expression was detected in all thyroid cancer samples and in 96.7% of healthy thyroid tissues; notably, the expression levels were similar in both groups. In addition, there was no correlation between SMYD3 expression and the aggressiveness of papillary thyroid cancer. In conclusion, overexpression of the EZH2 gene may be associated with the development of papillary thyroid cancer and EZH2 may be a potential therapeutic target in papillary thyroid cancer.

Introduction

Modifications to histone amino-terminals are significant for the regulation of chromatin structure, interaction with chromatin-associated proteins, transcription and DNA replication (13). Histone lysine methylases (KMTs) are responsible for modifications in amino-acid residues of the exposed N-terminal domain of histones by methylation of lysines. As a result, the gene is activated or repressed (2,3). Methyltransferases of mixed lineage leukemia (MLL) and the SET and MYND domain-containing protein (SMYD) family are involved in trimethylation of lysine 4 at histone 3 (3). Expression of SMYD family members is significantly altered in various human diseases (3,4). Their participation has been studied in cancer, embryonic heart development and inflammatory processes (4). The SMYD family consists of five members with a different structure from the other KMTs: The SET domain is split into two segments by an MYND domain, followed by a cysteine-rich post SET domain (1,3,5,6). SMYD3 was the first member of the SMYD family for which catalytic significance was also demonstrated for domains other than classical SET (3,7). SMYD3 was recently shown also to catalyze methylation of lysine 5 of histone 4 (3,8). Specific SMYD3 binding elements in the target DNA (5′-CCCTCC-3′ or 5′-GGAGGG-3′) are present in gene promoter regions below SMYD3, such as Nks2.8, WHT10B, and HTERT (1,911). SMYD3 activates transcription of several oncogenes (e.g. C-Met, JUND and Wnt10B), cell cycle regulating genes (e.g. CDK2 and β DNA topoisomerase) and genes responsible for signal transduction (e.g. RAB40C and GNRF2). However, SMYD3 inhibits the expression of some tumor suppressor genes (e.g. RIZ1) by epigenetic regulation (1,9,12,13). Increased SMYD3 expression is significant for cell viability, adhesion, migration and invasion (1,14). It correlates with poor prognosis in various types of cancer. The nucleus placed protein-coding gene SMYD3 is a selective transcription enhancer of oncogenes and the process of cell proliferation in liver and colon cancers. The mechanism is based on interaction with RNA Pol II and H3K4me3 and, in the case of liver tumors, is strongly associated with poor prognosis. Additionally, SMYD3 has an impact on Ras/ERK signaling in lung and pancreatic cancers by methylation of MAP3K2 kinase (3). A significant correlation has been found between the genetic variant with the variable number tandem repeat (VNTR) in the SMYD3 gene and the development of breast cancer in Jordanian women (15). Overexpression of SMYD3 also correlates with a more aggressive phenotype of prostate cancer (16). The role of the SMYD3 gene is also being studied in cholangiocarcinoma, esophageal squamous cell carcinoma, cervical, ovarian, bladder, gastric cancers, chronic lymphocytic leukemia and glioma (1726). No studies are being undertaken to evaluate SMYD3 expression in papillary thyroid cancers, while one previous study confirmed its overexpression in medullary thyroid cancers (24).

An enhancer of zeste homolog 2 (EZH2) is a histone methyltransferase, the catalytic subunit of the Polycomb 2 repression complex responsible for the trimethylation of histone H3 lysine 27 (H3K27me3) (27,28). Research on embryonic EZH2-zero (ESC) stem cells has shown residual H3K27me3, termed EZH1 methyltransferase. This may indicate at least partial compensation of both enzymes (2931). Genetic loss-of-function studies have demonstrated a role for EZH2 in the establishment and physiology of several cell types and tissues, such as the skin, heart and mammary gland (2933). Similar to SMYD3, EZH2 is highly expressed in various types of cancer, which is often also correlated with poor prognosis. The effect of EZH2 gene expression on carcinogenesis is the promotion of survival, proliferation, transformation of epithelium to mesenchyme, and the invasion and drug resistance of cancers. However, tumor-suppressive effects of EZH2 have also been identified. EZH2 has a significant impact on immune cells (27). The overexpression of EZH2 has been demonstrated in breast, prostate, endometrial, bladder, liver, lung, ovarian cancer, melanoma, glioblastoma and Natural killer/T-cell lymphoma. Gain-of-function mutations are present in Non-Hodgkin's lymphoma and melanoma. Through repression of the TIMP-3 metastatic suppressor gene, EZH2 leads to progression and spread in prostate and lung cancers and, through missense mutation in lymphomas, leads to increased function of the mutated protein (28).

These genes are currently undergoing extensive research in various types of cancers, including thyroid cancers. These are seen as the goals for targeted therapeutic strategies in oncology. Both genes have already been studied in medullary thyroid cancer (MTC) (24). In addition, research on the EZH2 gene has also been carried out on poorly differentiated (PDTC) and anaplastic thyroid carcinoma (ATC) (34), and also papillary thyroid cancer (35). Our study aimed to analyze EZH2 and SMYD3 gene expression in papillary thyroid cancer (PTC), the most common form of malignancy in this organ, and to correlate this with clinical outcome.

Material and methods

Tissue samples

Samples of resected thyroid tissue from consecutive patients were collected: papillary thyroid cancers and thyroid tissue from thyroids without cancer excised for nodular goiter. All patients underwent primary thyroid surgery. We excluded patients with mixed thyroid cancers. Tissue samples were stored in RNA protective medium at −80°C until reverse transcription-quantitative PCR (RT-qPCR) analysis. The Ethical Committee of Poznan University of Medical Sciences approved the study (approval no. 228/14) and each patient provided written informed consent.

Nucleic acid extraction and validation

RNA was isolated from tissue specimens using the Direct-zol RNA kit column system for high molecular weight RNA isolation according to the manufacturer's protocol (Zymo Research). In short, ~25 mg of tissue was homogenized in liquid nitrogen, and suspended in TriReagent (GenoPlast). After chloroform addition, the samples were centrifuged (12,000 × g, 15 min, 4°C) and the aqueous phase was transferred in the column. The isolation, following the protocol, finished with RNA recovery from silica matrix columns in pre-warmed water. The quality, quantity and purity of RNA were analyzed as described before (36) with the use of a NanoPhotometer® NP-80 (IMPLEN). The integrity was evaluated by electrophoretic separation in denaturing conditions.

RT-qPCR

Complementary to RNA DNA (cDNA) was synthesized in a three-step reaction conducted following the Transcriptor Reverse Transcriptase manufacturer's protocol (Roche Diagnostics GmbH) in a total volume of 20 µl. A mixture of 5 mM oligo(d)T10, RNA (1 µg) and RNase-, DNase- and pyrogen-free water was incubated for 10 min at 65°C. Subsequently, the samples were chilled. Subsequently, 10 U/µl ribonuclease inhibitor (RNasin, Roche Diagnostics GmbH), 10 U/µl of transcriptor reverse transcriptase (Roche Diagnostics GmbH), 100 mM deoxyribonucleotide triphosphates (Novayzm) and 1× reaction buffer (Roche Diagnostics GmbH) were added. The subsequent steps of cDNA synthesis had been described earlier (36).

RNA expression pattern analysis was performed using a LightCycler® 2.0 (Roche Diagnostics GmbH). Primer sequences and TaqMan® hydrolysis probe positions for the EZH2 and SMYD3 were determined using the Roche Universal ProbeLibrary (UPL) Assay Design Center (http://qpcr.probefinder.com; last accessed on May 10, 2017). Ensembl (http://www.ensembl.org/), and protein-coding sequences for EZH2 (ENST00000320356.7, ENST00000460911.5, ENST00000476773.5, ENST00000478654.5, ENST00000350995.6, ENST00000483967.5) were used to design the primers and hydrolysis probes (Roche TaqMan Probe UPL #35; cat. no. 04687680001). The forward (5′-tgtggatactcctccaaggaa-3′) and reverse (5′-gaggagccgtcctttttca-3′) primers flank the 90 nt amplicon (Fig. 1A). The set of forward (5′-cctgcctttgacctttttga-3′) and reverse (5′-agatactgggatataggccaacac-3′) primers' for SMYD3 covered the 106 nt amplicons with the TaqMan UPL #4 in between (Roche Diagnostics GmbH; cat. no. 04685016001). The assay was designed for both transcript variants (NCBI NM_001167740 and NM_022743.2) (Fig. 1B). The hypoxanthine-guanine phosphoribosyltransferase (HPRT) gene assay (Roche cat. no. 05532957001) served as an internal control.

The quantitative polymerase chain reactions had been standardized earlier and conducted as described before (36) in a total volume of 20 µl with a 1× LightCycler® FastStart TaqMan® Probe Master mix. Each reaction was performed in duplicate on independently synthesized cDNA, and the mean values were used for statistical analyses. Reaction efficiencies were obtained from the genes' standard curves (36). Raw data for threshold values were analyzed by comparing them to appropriately selected standard curves and the reference gene assay with the use of LC 5.0.0.38 software, and presented as concentration ratios (Cr).

Statistical analysis

Statistical analysis was performed with MedCalc Statistical Software version 19.1.5 (MedCalc Software bv; https://www.medcalc.org; 2020). The D'Agostino-Pearson test analyzed normality. P<0.05 was considered to indicate a statistically significant difference. The Mann-Whitney test was used to compare non-normally distributed parameters between the study and control groups, as well as between analyzed subgroups. When data followed a normal distribution, Student's t-test was used for comparison between groups. The χ2 test was applied to compare descriptive parameters. The Kruskal-Wallis test with Conover post-hoc test was used to compare gene expression between thyroid cancer samples staged 1, 2, 3, and 4. The Spearman's correlation coefficient test was used to find relationships between analyzed parameters.

Results

Patient characteristics

The study group consisted of 62 patients with papillary thyroid cancers. There were 30 tissue samples in the healthy control group. Clinical data are presented in Table I. The study, and the control groups did not differ according to patients' age or sex.

Table I.

Clinical data of the study and the control groups.

Table I.

Clinical data of the study and the control groups.

CharacteristicsPapillary thyroid cancer group (n=62)Control group (n=30)P-value
Mean ± SD age, years51±1646±160.17
Sex 0.15
  Female4325
  Male19  5
Histological variant
  Conventional54
  Follicular  4
  Oncocytic  3
  Tall cell  1
Staging at diagnosis
  I35
  II12
  III13
  IV12
Metastases to the lymph nodes (%)14 (22.6)
Multifocality (%)27 (43.5)
Distant metastases (%)1 (1.6)
EZH2 expression

EZH2 expression was found in all thyroid cancer samples and 25 out of 30 samples of benign lesions. We found EZH2 overexpression in thyroid cancers (P=0.0002) (Fig. 2). EZH2 expression positively correlated with tumor stage (P<0.0001; r=0.504; Fig. 3), and multiple comparison analysis revealed the highest expression in samples staged pT4 (P=0.0001) (Fig. 4). We did not observe EZH2 overexpression in patients with lymph node involvement (Fig. 5), and there was no association between EZH2 expression and multifocality (P=0.13 and P=0.49, respectively). Also, patients' age did not correlate with EZH2 expression levels (P=0.66) (Fig. 6).

SMYD3 expression

SMYD3 expression was found in all thyroid cancer samples and 29 out of 30 healthy tissues, and the expression levels were similar in both groups (P=0.90) (Fig. 7). Also, there were no differences in SMYD3 expression between tumors staged pT1, pT2, pT3 or pT4 (P=0.37) (Fig. 8). Patients with metastases to the lymph nodes did not have higher SMYD3 expression than those without (P=0.83) (Fig. 9). We did not observe any correlation between SMYD3 expression and multifocality (P=0.45).

Discussion

We found histone methyltransferase EZH2 overexpression in papillary thyroid cancer (PTC), while SMYD3 expression was not elevated. EZH2 gene expression was found in all papillary thyroid cancer samples, but also in most, as many as five sixths of healthy thyroid tissue samples. These were significantly higher expression rates, in both the study and control groups, than those obtained by Xue et al (35). However, they examined the expression of the EZH2 gene both by real-time PCR, as in our study, and immunohistochemistry (IHC), and they presented the expression percentages for IHC (35). However, in papillary thyroid carcinomas, statistically significant overexpression of the EZH2 gene was found in our study. Therefore, the EZH2 gene may be associated with the development of papillary thyroid cancer. Xue et al (35) obtained similar results. This is the case in papillary thyroid cancer, as well as in other thyroid cancers, as shown in Table II (24,34,35).

Table II.

Studies on EZH2 gene in thyroid cancers.

Table II.

Studies on EZH2 gene in thyroid cancers.

First author, yearNumber of patients, type of thyroid cancerNumber of patients in the control groupAnalytical techniqueResultsRefs.
Masudo, 201867 cases of PDTC and 48 cases of ATC30 adjacent healthy and differentiated thyroid carcinoma tissueIHCEZH2 was expressed in PDTC and ATC, but not in the normal thyroid gland or DTC; EZH-positivity increased in the order of DTC, PDTC, and ATC (P<0.01); higher EZH2 expression correlated with more reduced survival in PDTC (P=0.004) and ATC (P=0.166)(34)
Sponziello, 201454 MTCs; 13 familial MTCs and 41 sporadic forms; 33 hosted an RET mutation and 13 an RAS somatic mutationqPCRA significant increase in EZH2 and SMYD3 gene expression in more aggressive diseases (i.e. occurrence of metastases; persistent disease; disease-related death); the increase in EZH2 and SMYD3 did not correlate with the mutational status of RET or RAS genes(24)
Xue, 201965 PTCs30 adjacent healthy thyroid tissuesqPCR and IHCHigher EZH2 expression in PTC tissues than in healthy thyroid tissues; EZH2 expression is associated with lymph node metastasis and is recurrent; inhibition of EZH2 in PTC cell lines downregulates cellular proliferation and migration. PTC is a disease with a high incidence in females and E2-ERα upregulates EZH2 expression(35)

[i] DTC, differentiated thyroid cancer; PDTC, poorly differentiated thyroid cancer; ATC, anaplastic thyroid carcinoma; MTCs, medullary thyroid cancer; PTC, papillary thyroid cancer; IHC, immunohistochemistry; qPCR, quantitative PCR.

The expression of the EZH2 gene positively correlated with the tumor stage, in the case of tumorous staged pT4, it was the highest. Xue et al (35) did not observe statistically significant differences between tumors <=1 cm and tumors >1 cm, or between those that extended beyond the thyroid tissue and those that did not. However, we did not observe EZH2 overexpression in patients with lymph node involvement, as had been obtained by Xue et al (35). Also, we did not find a relationship between EZH2 expression and multifocality. In both studies, age did not significantly correlate with EZH2 gene expression. Correlation with aggressiveness in thyroid cancers was described by Sponziello et al (24) based on their study on medullary thyroid carcinomas (MTC). Sponziello et al (24) examined the expression of epigenetic regulators in medullary thyroid carcinomas (MTCs) and correlated this with clinical outcome and RET or RAS mutational status. In the case of a more aggressive disease, they noted a significant increase in EZH2 and SMYD3 gene expression (more than 3 and 2-fold, respectively). They determined the aggressiveness of the disease, according to the current guidelines (37), based on the occurrence of lymph nodes and distant metastases, persistence after primary treatment and disease-related death. Noticeably, they did not observe a significant correlation between the overexpression of EZH2 and SMYD3 and the mutational status of RET or RAS genes. Therefore, the researchers suggested that EZH2 and SMYD3 mRNA expression may be useful prognostic biomarkers, and further studies are needed to investigate their possibility of use in therapy of MTC patients (24). Also, Masudo et al (34) claim that EZH2 overexpression may be a useful prognostic marker for more aggressive thyroid cancers. This is justified by their statistically significant increase in EZH-positivity in order from differentiated (DTC), then poorly differentiated (PDTC) to anaplastic forms of thyroid cancers (ATC). Also, higher EZH2 expression correlated with more reduced survival in the case of less differentiated cancers (34). Similarly, the prognostic significance of the EZH2 gene has already been observed in cancers of other organs, including the prostate, lung or lymphomas (28). Currently, increasing numbers of studies are being developed that expand the range of thyroid cancers tested, as well as molecular mechanisms associated with the impact of the EZH2 gene on carcinogenesis (38). EZH2 is important in medullary thyroid cancer by affecting ERK and AKT signaling pathways. It also controls genes of the Wnt/β-catenin (24). It has been observed that increased expression of EZH2 in PTC cell lines upregulates cellular proliferation and migration by affecting the E2-ERα signaling pathway (35). Researchers have observed the role of long noncoding RNA PVT1 in the development of thyroid cancer through its involvement in the modulation of cell proliferation by recruiting EZH2 and regulating the thyroid-stimulating hormone receptor (TSHR) (39). In their search for differences between thyroid follicular cancer and thyroid follicular adenoma scientists have used network-based genetic profiling, which includes the EZH2 gene (40).

Overexpression of SMYD3 was not characteristic of papillary thyroid cancer in our study. Expression of this gene was observed in every test sample and in almost every control sample. Moreover, expression levels in study and control samples were similar. There was also no correlation between SMYD3 gene expression and the markers of greater disease aggression. No studies on the expression of the SMYD3 gene in papillary thyroid cancer have previously been performed. However, our study was justified due to the overexpression of both the EZH2 and SMYD3 genes observed by Sponziello et al, as well as the correlation of both genes with greater aggressiveness of medullary thyroid cancers (MTCs) (24). A similar correlation between the expression level of these genes and tumor aggression has been observed in cancers of other organs, e.g. liver or prostate (3,16). Chemical probes are being developed to target SMYD3 selectively (41).

In both the study and the control groups, the majority of patients were women. It has been known for many years that PTC is a disease with a high prevalence in women, which is also confirmed by the current research. This tendency is emphasized by Xue et al (35) who recently published their research on the EZH2 gene in PTC on similarly numerous research (n=65) and control (n=30) groups. Moreover, the latest trends show that among women, the highest increase in incidence was observed in 2014: 22.2 new cases were diagnosed per 100,000 people (42). Also, researchers have noted that the disproportion between women and men is particularly intensified during the reproductive period (35,43). It has been found that estrogen can increase PTC growth, progression and metastasis and that E2 treatment can significantly increase EZH2 levels (35,44,45). The effectiveness of the specific EZH2 inhibitor GSK126 also confirms the above observations (35). Most, as many as 25 thyroid cancers were in stage I. This means that often the tumor was not larger than 2 cm and did not grow outside the thyroid gland (37). Samples in stages II-IV were similarly numerous. In thyroid cancers, metastases to the lymph nodes were observed in 23% of patients. Although PTC is often localized, the lymphatic tract is the most common for metastasis, and the site of metastasis is usually local lymph nodes (46). Literature data show the influence of both genes on the fate of individual cells, so it would be reasonable to compare cells from the same thyroid that are neoplastic to those unchanged. On the other hand, thyroid cancers might be multifocal, and molecular alterations proceed cancer. So it could also potentially affect achieved results.

Our results indicate that overexpression of the EZH2 gene may be associated with the development of papillary thyroid cancer. Therefore, the EZH2 gene may also be a potential therapeutic target in papillary thyroid cancer.

Acknowledgements

Not applicable.

Funding

The National Science Center partially supported this work in Poland (grant no. DEC 2012/07/N/NZ5/01736).

Availability of data and materials

The datasets used and/or analyzed during the current study are available from the corresponding author on reasonable request.

Authors' contributions

NSG designed the study, was involved in data collection, analyzed data, and wrote and revised the manuscript. SS and PZ conducted the manuscript preparation and data analysis/interpretation. MA carried out the experimental studies and data analysis. AC was involved in data collection and data analysis. PG conceived the study and was involved in data analysis. MR made substantial contribution to acquisition of samples and clinical data, and revised the paper. NSG and MA confirm the authenticity of all the raw data. All authors read and approved the final manuscript.

Ethics approval and consent to participate

The Ethical Committee of Poznan University of Medical Sciences approved the present study (approval no. 228/14). Written informed consent was obtained from all patients.

Patient consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

References

1 

Zou JN, Wang SZ, Yang JS, Luo XG, Xie JH and Xi T: Knockdown of SMYD3 by RNA interference down-regulates c-Met expression and inhibits cells migration and invasion induced by HGF. Cancer Lett. 280:78–85. 2009. View Article : Google Scholar : PubMed/NCBI

2 

Kouzarides T: Chromatin modifications and their function. Cell. 128:693–705. 2007. View Article : Google Scholar : PubMed/NCBI

3 

Giakountis A, Moulos P, Sarris ME, Hatzis P and Talianidis I: Smyd3-associated regulatory pathways in cancer. Semin Cancer Biol. 42:70–80. 2017. View Article : Google Scholar : PubMed/NCBI

4 

Varier RA and Timmers HT: Histone lysine methylation and demethylation pathways in cancer. Biochim Biophys Acta. 1815:75–89. 2011.PubMed/NCBI

5 

Spellmon N, Holcomb J, Trescott L, Sirinupong N and Yang Z: Structure and function of SET and MYND domain-containing proteins. Int J Mol Sci. 16:1406–1428. 2015. View Article : Google Scholar : PubMed/NCBI

6 

Foreman KW, Brown M, Park F, Emtage S, Harriss J, Das C, Zhu L, Crew A, Arnold L, Shaaban S and Tucker P: Structural and functional profiling of the human histone methyltransferase SMYD3. PLoS One. 6:e222902011. View Article : Google Scholar : PubMed/NCBI

7 

Xu S, Wu J, Sun B, Zhong C and Ding J: Structural and biochemical studies of human lysine methyltransferase Smyd3 reveal the important functional roles of its post-SET and TPR domains and the regulation of its activity by DNA binding. Nucleic acids Res. 39:4438–4449. 2011. View Article : Google Scholar : PubMed/NCBI

8 

Van Aller GS, Reynoird N, Barbash O, Huddleston M, Liu S, Zmoos AF, McDevitt P, Sinnamon R, Le B, Mas G, et al: Smyd3 regulates cancer cell phenotypes and catalyzes histone H4 lysine 5 methylation. Epigenetics. 7:340–343. 2012. View Article : Google Scholar : PubMed/NCBI

9 

Hamamoto R, Furukawa Y, Morita M, Iimura Y, Silva FP, Li M, Yagyu R and Nakamura Y: SMYD3 encodes a histone methyltransferase involved in the proliferation of cancer cells. Nat Cell Biol. 6:731–740. 2004. View Article : Google Scholar : PubMed/NCBI

10 

Hamamoto R, Silva FP, Tsuge M, Nishidate T, Katagiri T, Nakamura Y and Furukawa Y: Enhanced SMYD3 expression is essential for the growth of breast cancer cells. Cancer Sci. 97:113–118. 2006. View Article : Google Scholar : PubMed/NCBI

11 

Liu C, Fang X, Ge Z, Jalink M, Kyo S, Björkholm M, Gruber A, Sjöberg J and Xu D: The telomerase reverse transcriptase (hTERT) gene is a direct target of the histone methyltransferase SMYD3. Cancer Res. 67:2626–2631. 2007. View Article : Google Scholar : PubMed/NCBI

12 

Guo N, Chen R, Li Z, Liu Y, Cheng D, Zhou Q, Zhou J and Lin Q: Hepatitis C virus core upregulates the methylation status of the RASSF1A promoter through regulation of SMYD3 in hilar cholangiocarcinoma cells. Acta Biochim Biophys Sin. 43:354–361. 2011. View Article : Google Scholar : PubMed/NCBI

13 

Tsuge M, Hamamoto R, Silva FP, Ohnishi Y, Chayama K, Kamatani N, Furukawa Y and Nakamura Y: A variable number of tandem repeats polymorphism in an E2F-1 binding element in the 5′ flanking region of SMYD3 is a risk factor for human cancers. Nat Genet. 37:1104–1107. 2005. View Article : Google Scholar : PubMed/NCBI

14 

Luo XG, Ding Y, Zhou QF, Ye L, Wang SZ and Xi T: SET and MYND domain-containing protein 3 decreases sensitivity to dexamethasone and stimulates cell adhesion and migration in NIH3T3 cells. J Biosci Bioeng. 103:444–450. 2007. View Article : Google Scholar : PubMed/NCBI

15 

AL-Eitan LN and Rababa'h DM: Correlation between a variable number tandem repeat (VNTR) polymorphism in SMYD3 gene and breast cancer: A genotype-phenotype study. Gene. 728:1442812020. View Article : Google Scholar : PubMed/NCBI

16 

Vieira FQ, Costa-Pinheiro P, Almeida-Rios D, Graça I, Monteiro-Reis S, Simões-Sousa S, Carneiro I, Sousa EJ, Godinho MI, Baltazar F, et al: SMYD3 contributes to a more aggressive phenotype of prostate cancer and targets Cyclin D2 through H4K20me3. Oncotarget. 6:13644–13657. 2015. View Article : Google Scholar : PubMed/NCBI

17 

Zeng B, Li Z, Chen R, Guo N, Zhou J, Zhou Q, Lin Q, Cheng D, Liao Q, Zheng L and Gong Y: Epigenetic regulation of miR-124 by hepatitis C virus core protein promotes migration and invasion of intrahepatic cholangiocarcinoma cells by targeting SMYD3. FEBS Lett. 586:3271–3278. 2012. View Article : Google Scholar : PubMed/NCBI

18 

Zhu Y, Zhu MX, Zhang XD, Xu XE, Wu ZY, Liao LD, Li LY, Xie YM, Wu JY, Zou HY, et al: SMYD3 stimulates EZR and LOXL2 transcription to enhance proliferation, migration, and invasion in esophageal squamous cell carcinoma. Hum Pathol. 52:153–163. 2016. View Article : Google Scholar : PubMed/NCBI

19 

Wang SZ, Luo XG, Shen J, Zou JN, Lu YH and Xi T: Knockdown of SMYD3 by RNA interference inhibits cervical carcinoma cell growth and invasion in vitro. BMB Rep. 41:294–299. 2008. View Article : Google Scholar : PubMed/NCBI

20 

Jiang Y, Lyu T, Che X, Jia N, Li Q and Feng W: Overexpression of SMYD3 in ovarian cancer is associated with ovarian cancer proliferation and apoptosis via methylating H3K4 and H4K20. J Cancer. 10:4072–4084. 2019. View Article : Google Scholar : PubMed/NCBI

21 

Wu X, Xu Q, Chen P, Yu C, Ye L, Huang C and Li T: Effect of SMYD3 on biological behavior and H3K4 methylation in bladder cancer. Cancer Manag Res. 11:8125–8133. 2019. View Article : Google Scholar : PubMed/NCBI

22 

Wang L, Wang QT, Liu YP, Dong QQ, Hu HJ, Miao Z, Li S, Liu Y, Zhou H, Zhang TC, et al: ATM signaling pathway is implicated in the SMYD3-mediated proliferation and migration of gastric cancer cells. J Gastric Cancer. 17:295–305. 2017. View Article : Google Scholar : PubMed/NCBI

23 

Khatami F and Tavangar SM: Genetic and epigenetic of medullary thyroid cancer. Iran Biomed J. 22:142–150. 2018.PubMed/NCBI

24 

Sponziello M, Durante C, Boichard A, Dima M, Puppin C, Verrienti A, Tamburrano G, Di Rocco G, Redler A, Lacroix L, et al: Epigenetic-related gene expression profile in medullary thyroid cancer revealed the overexpression of the histone methyltransferases EZH2 and SMYD3 in aggressive tumours. Mol Cell Endocrinol. 392:8–13. 2014. View Article : Google Scholar : PubMed/NCBI

25 

Lin F, Wu D, Fang D, Chen Y, Zhou H and Ou C: STAT3-induced SMYD3 transcription enhances chronic lymphocytic leukemia cell growth in vitro and in vivo. Inflamm Res. 68:739–749. 2019. View Article : Google Scholar : PubMed/NCBI

26 

Dai B, Wan W, Zhang P, Zhang Y, Pan C, Meng G, Xiao X, Wu Z, Jia W, Zhang J and Zhang L: SET and MYND domain-containing protein 3 is overexpressed in human glioma and contributes to tumorigenicity. Oncol Rep. 34:2722–2730. 2015. View Article : Google Scholar : PubMed/NCBI

27 

Gan L, Yang Y, Li Q, Feng Y, Liu T and Guo W: Epigenetic regulation of cancer progression by EZH2: From biological insights to therapeutic potential. Biomark Res. 6:102018. View Article : Google Scholar : PubMed/NCBI

28 

Kim KH and Roberts CW: Targeting EZH2 in cancer. Nat Med. 22:128–134. 2016. View Article : Google Scholar : PubMed/NCBI

29 

Bae WK and Hennighausen L: Canonical and non-canonical roles of the histone methyltransferase EZH2 in mammary development and cancer. Mol Cell Endocrinol. 382:593–597. 2014. View Article : Google Scholar : PubMed/NCBI

30 

Shen X, Liu Y, Hsu YJ, Fujiwara Y, Kim J, Mao X, Yuan GC and Orkin SH: EZH1 mediates methylation on histone H3 lysine 27 and complements EZH2 in maintaining stem cell identity and executing pluripotency. Mol Cell. 32:491–502. 2008. View Article : Google Scholar : PubMed/NCBI

31 

Ezhkova E, Lien WH, Stokes N, Pasolli HA, Silva JM and Fuchs E: EZH1 and EZH2 cogovern histone H3K27 trimethylation and are essential for hair follicle homeostasis and wound repair. Genes Dev. 25:485–498. 2011. View Article : Google Scholar : PubMed/NCBI

32 

Pal B, Bouras T, Shi W, Vaillant F, Sheridan JM, Fu N, Breslin K, Jiang K, Ritchie ME, Young M, et al: Global changes in the mammary epigenome are induced by hormonal cues and coordinated by Ezh2. Cell Rep. 3:411–426. 2013. View Article : Google Scholar : PubMed/NCBI

33 

Laible G, Wolf A, Dorn R, Reuter G, Nislow C, Lebersorger A, Popkin D, Pillus L and Jenuwein T: Mammalian homologues of the Polycomb-group gene Enhancer of zeste mediate gene silencing in Drosophila heterochromatin and at S. cerevisiae telomeres. EMBO J. 16:3219–3232. 1997. View Article : Google Scholar : PubMed/NCBI

34 

Masudo K, Suganuma N, Nakayama H, Oshima T, Rino Y, Iwasaki H, Matsuzu K, Sugino K, Ito K, Kondo T, et al: EZH2 overexpression as a useful prognostic marker for aggressive Behaviour in thyroid cancer. In vivo. 32:25–31. 2018.PubMed/NCBI

35 

Xue L, Yan H, Chen Y, Zhang Q, Xie X, Ding X, Wang X, Qian Z, Xiao F, Song Z, et al: EZH2 upregulation by ERα induces proliferation and migration of papillary thyroid carcinoma. BMC cancer. 19:10942019. View Article : Google Scholar : PubMed/NCBI

36 

Andrusiewicz M, Slowikowski B, Skibinska I, Wolun-Cholewa M and Dera-Szymanowska A: Selection of reliable reference genes in eutopic and ectopic endometrium for quantitative expression studies. Biomed Pharmacother. 78:66–73. 2016. View Article : Google Scholar : PubMed/NCBI

37 

Haddad RI, Nasr C, Bischoff L, Busaidy NL, Byrd D, Callender G, Dickson P, Duh QY, Ehya H, Goldner W, et al: NCCN guidelines insights: Thyroid carcinoma, version 2.2018. J Natl Compr Canc Netw. 16:1429–1440. 2018. View Article : Google Scholar : PubMed/NCBI

38 

Wang LJ and Cai HQ: miR-1258: A novel microRNA that controls TMPRSS4 expression is associated with malignant progression of papillary thyroid carcinoma. Endokrynol Pol. 71:146–152. 2020. View Article : Google Scholar : PubMed/NCBI

39 

Zhou Q, Chen J, Feng J and Wang J: Long noncoding RNA PVT1 modulates thyroid cancer cell proliferation by recruiting EZH2 and regulating thyroid-stimulating hormone receptor (TSHR). Tumour Biol. 37:3105–3113. 2016. View Article : Google Scholar : PubMed/NCBI

40 

Hossain MA, Asa TA, Rahman MM, Uddin S, Moustafa AA, Quinn JMW and Moni MA: Network-based genetic profiling reveals cellular pathway differences between follicular thyroid carcinoma and follicular thyroid adenoma. Int J Environ Res Public Health. 17:13732020. View Article : Google Scholar

41 

Fabini E, Manoni E, Ferroni C, Rio AD and Bartolini M: Small-molecule inhibitors of lysine methyltransferases SMYD2 and SMYD3: Current trends. Future Med Chem. 11:901–921. 2019. View Article : Google Scholar : PubMed/NCBI

42 

Roman BR, Morris LG and Davies L: The thyroid cancer epidemic, 2017 perspective. Curr Opin Endocrinol Diabetes Obes. 24:332–336. 2017. View Article : Google Scholar : PubMed/NCBI

43 

Al-Zahrani AS and Ravichandran K: Epidemiology of thyroid cancer: A review with special reference to Gulf cooperation council (GCC) states. Gulf J Oncolog. 17–28. 2007.PubMed/NCBI

44 

Kinoshita Y, Takasu K, Yuri T, Yoshizawa K, Emoto Y, Tsubura A and Shikata N: Estrogen receptor-and progesterone receptor-positive diffuse sclerosing variant of papillary thyroid carcinoma: A case report. Case Rep Oncol. 6:216–223. 2013. View Article : Google Scholar : PubMed/NCBI

45 

Huang Y, Dong W, Li J, Zhang H, Shan Z and Teng W: Differential expression patterns and clinical significance of estrogen receptor-alpha and beta in papillary thyroid carcinoma. BMC cancer. 14:3832014. View Article : Google Scholar : PubMed/NCBI

46 

Lu J, Gao J, Zhang J, Sun J, Wu H, Shi X, Teng L and Liang Z: Association between BRAF V600E mutation and regional lymph node metastasis in papillary thyroid carcinoma. Int J Clin Exp Pathol. 8:793–799. 2015.PubMed/NCBI

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May-2021
Volume 21 Issue 5

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Online ISSN:1792-1082

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Copy and paste a formatted citation
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Spandidos Publications style
Sawicka‑Gutaj N, Shawkat S, Andrusiewicz M, Ziółkowska P, Czarnywojtek A, Gut P and Ruchała M: <em>EZH2</em> and <em>SMYD3</em> expression in papillary thyroid cancer. Oncol Lett 21: 342, 2021
APA
Sawicka‑Gutaj, N., Shawkat, S., Andrusiewicz, M., Ziółkowska, P., Czarnywojtek, A., Gut, P., & Ruchała, M. (2021). <em>EZH2</em> and <em>SMYD3</em> expression in papillary thyroid cancer. Oncology Letters, 21, 342. https://doi.org/10.3892/ol.2021.12603
MLA
Sawicka‑Gutaj, N., Shawkat, S., Andrusiewicz, M., Ziółkowska, P., Czarnywojtek, A., Gut, P., Ruchała, M."<em>EZH2</em> and <em>SMYD3</em> expression in papillary thyroid cancer". Oncology Letters 21.5 (2021): 342.
Chicago
Sawicka‑Gutaj, N., Shawkat, S., Andrusiewicz, M., Ziółkowska, P., Czarnywojtek, A., Gut, P., Ruchała, M."<em>EZH2</em> and <em>SMYD3</em> expression in papillary thyroid cancer". Oncology Letters 21, no. 5 (2021): 342. https://doi.org/10.3892/ol.2021.12603