EZH2 inhibition promotes methyl jasmonate‑induced apoptosis of human colorectal cancer through the Wnt/β‑catenin pathway

Retraction in: /10.3892/ol.2021.12832

  • Authors:
    • Yao Wang
    • Li Fan
    • Chunguo Cui
    • Yongkun Wang
    • Tingting Liang
  • View Affiliations

  • Published online on: May 22, 2018     https://doi.org/10.3892/ol.2018.8779
  • Pages: 1231-1236
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Abstract

Methyl jasmonate potentially induces the differentiation of human myeloid leukemia cells and inhibits their proliferation; it may induce the differentiation and apoptosis of human lymphocytic leukemia cells, but does not exert a damaging effect on normal lymphocytes. In the present study, the anticancer effect of methyl jasmonate on human colorectal cancer cells was investigated. Cell viability and apoptosis was assessed using a Cell Counting kit‑8 assay and flow cytometry, respectively. Methyl jasmonate suppressed cell viability and induced apoptosis in human colorectal cancer cells. Additionally, methyl jasmonate increased the activation of caspase‑3, inhibited the expression levels of enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) and the Wnt/β‑catenin pathway in human colorectal cancer. Downregulation of EZH2 expression enhanced the anticancer effect of methyl jasmonate on human colorectal cancer cells through suppression of the Wnt/β‑catenin pathway. Thus, EZH2 downregulation promotes the anticancer effect of methyl jasmonate by inducing apoptosis in human colorectal cancer cells through the Wnt/β‑catenin pathway.

Introduction

Colorectal cancer is a malignant tumor with morbidity ranking as the third highest globally; patients exhibited a 5-year survival rate of ~50% in 2014 (1). The primary causes of mortality are cancer metastasis to the liver and the lungs (2). The primary lesion size, differentiation degree and degree of lymphatic metastasis of the tumor may influence disease prognosis (2). The genesis and development of colorectal cancer is a complex process with multiple stages, including carcinogenic gene activation and cancer suppressor gene inactivation, causing the tissue to progress from normal colon mucosa to adenoma and then to adenocarcinoma (3). In spite of the numerous different clinical treatment strategies, including surgical resection, chemotherapy and radiotherapy, treatment-resistance, relapse and metastasis remain the leading cause of mortality for patients with splenoma (2,4). Hence, a worthwhile focus for the prophylaxis and treatment of colorectal cancer is the investigation of its underlying molecular mechanism, which is of notable practical significance (5).

Enhancer of zeste 2 polycomb repressive complex 2 subunit (EZH2) is a novel polycomb-group gene identified in Drosophila melanogaster; in 2000, its chromosomal locus was determined to be 7q35 in humans (6). Previous studies revealed that the EZH2 gene participated in cellular growth regulation (6,7). The mechanism underlying the function of EZH2 function was the inhibition of the Wnt signaling pathway in chromatin and the promotion of cell proliferation (7,8). Furthermore, as a transcription inhibition factor, EZH2 influenced the activity of multiple genes at the gene level; most notably, it inhibited tumor metastasis genes (including phosphoinositide, protein kinase B and matrix metalloproteinases), aiding the promotion of infiltration and migration of cancer cells (7,8).

Wnt signaling pathway serves notable functions in numerous different life events, including biological development, cell transportation and apoptosis (9). A previous study suggested that the Wnt pathway has at least three branches, including the canonical Wnt pathway, termed the Wnt/β-catenin pathway (10). At present, the majority of research is focused on the Wnt/β-catenin signaling pathway (11). Numerous clinical and experimental studies confirmed that the abnormal activation of the Wnt/β-catenin signaling pathway is closely associated with the occurrence and development of a tumor, including colorectal, breast, lung, endothelial-like ovarian, prostrate, endometrial, primary liver and thyroid cancer, and melanoma (11,12).

Methyl jasmonate is a salicylic acid isolated from jasmine (1315). Research revealed that methyl jasmonate could be used to treat skin fungal infection, in addition to possessing antitumor and anti-angiogenesis effects, which may inhibit the proliferation of numerous different types of cancer cells and induce cell apoptosis, including in gastric carcinoma, lung cancer, colon cancer, cervical cancer and melanoma (1315). The mechanism of action of methyl jasmonate may be associated with the inactivation of free radicals, the activation of cyclin and the activation of cyclin-dependent kinase (16). Additionally, methyl jasmonate may influence the tumor protein p53 pathway, caspase activity and B-cell lymphoma-2-associated X protein signal transduction pathway closely associated with tumorigenesis (16). In the present study, the anticancer effect of methyl jasmonate via induction of apoptosis in human colorectal cancer cells via the downregulation of EZH2 expression was examined.

Materials and methods

Cell culture

The human bladder cancer T24 cell line was obtained from the Shanghai Cell Bank of the Chinese Academy of Sciences (Shanghai, China) and cultured in RPMI-1640 medium (Gibco; Thermo Fisher Scientific, Inc., Waltham, MA, USA) supplemented with 10% (v/v) fetal bovine serum (Hyclone; GE Healthcare Life Sciences, Logan, UT, USA) at 37°C in a humidified incubator under 5% CO2. GSK343, an EZH2 inhibitor (1 nM; MedChemExpress LLC, Monmouth Junction, NJ, USA) and 2.0 mM methyl jasmonate were added to the cells for 48 h at 37°C.

Cell viability assay and cytotoxicity

T24 cells were seeded in a 96-well plate at a density of 1×104 cells per well and cultured with 5 mM dimethyl sulfoxide (DMSO) or methyl jasmonate (0.5, 0.75, 1.5 and 2.0 mM, Sigma-Aldrich; Merck KGaA, Darmstadt, Germany) for different periods of time (0, 24, 48 and 72 h). A total of 10 µl Cell Counting kit-8 (CCK-8; Dojindo Molecular Technologies, Inc., Kumamoto, Japan) solution was added into every well and incubated for additional 2 h at 37°C in the dark. Cell viability was detected at 450 nm using a microplate reader. Lactate dehydrogenase (LDH; Beyotime Institute of Biotechnology, Jiangsu, China) was added into every well and incubated for additional 2 h at 37°C in the dark. Cytotoxicity was detected at 490 nm using a microplate reader.

Quantification of apoptosis rates

T24 cells were seeded in a 96-well plate at a density of 2×106 cells per well and cultured with DMSO (5 mM) or methyl jasmonate (0.75, 1.5 and 2.0 mM) for 48 h. Apoptotic rates were assessed using flow cytometry following fluorescein isothiocyanate-conjugated annexin V and propidium iodide staining (BD Pharmingen FITC Annexin V; cat. no. 556420; BD Pharmingen; BD Biosciences, Franklin Lakes, NJ, USA) at room temperature for 15 min, according to the manufacturer's protocol. Apoptosis rates were analyzed using flow cytometry (FACScan; BD Biosciences) and FlowJo version 7.6.1 (FlowJo LLC, Ashland, OR, USA).

Quantification of caspase-3 activity

T24 cells were seeded in a 96-well plate at a density of 1×104 cells per well and cultured with DMSO (5 mM) or methyl jasmonate (0.75, 1.5 and 2.0 mM) for 48 h. Caspase-3 activity was analyzed using a Caspase-3 Activity Assay kit (Beyotime Institute of Biotechnology), according to the manufacturer's protocol.

Western blot analysis

T24 cells were seeded in a 96-well plate at a density of 1×104 cells per well and cultured with DMSO (5 mM) or methyl jasmonate (0.75, 1.5 and 2.0 mM) for 48 h at 37°C. T24 cells were collected, and lysed with an RIPA buffer (Promega Corporation, Madison, WI, USA). Protein concentration was determined using a BCA Protein Assay kit (Thermo Fisher Scientific, Inc.). A total of 50 µg total protein were separated using 10–12% SDS-PAGE and were transferred onto polyvinylidene difluoride membranes. Alternative immunoblot analysis was performed using anti-EZH2 antibodies (sc-25383; 1:3,000; Santa Cruz Biotechnology, Inc., Dallas, TX, USA) and β-actin antibodies (sc-7210; 1:2,000; Santa Cruz Biotechnology, Inc.) at 4°C overnight after blocking with 5% non-fat in TBST for 1 h at 37°C. Immunoreactive bands were washed with 0.1% Tween TBST for 15 min, visualized by using the goat anti-rabbit IgG specific horseradish peroxidase-conjugated secondary antibody (sc-2004, 1:5,000; Santa Cruz Biotechnology, Inc.) for 1 h at 37°C and an electrochemiluminesence system (BeyoECL Moon; Beyotime Institute of Biotechnology). Protein expression was quantified from the band density using Image Lab 3.0 (Bio-Rad Laboratories, Inc., Hercules, CA, USA).

Statistical analysis

Data are presented as the mean ± standard deviation using SPSS version 17.0 (SPSS, Inc., Chicago, IL, USA). Statistical analyses were performed using SPSS version 17.0 (SPSS, Inc.). One-way analysis of variance followed by Dunnett's test was used to conduct multiple comparisons. P<0.05 was considered to indicate a statistically significant difference.

Results

Methyl jasmonate suppresses the viability of human colorectal cancer cells

The chemical structure of methyl jasmonate is presented in Fig. 1. To identify the effect of methyl jasmonate on the viability of human colorectal cancer cells, a CCK-8 assay was used to analyze the anticancer effects. As presented in Fig. 2, treatment with 0.75, 1.5 or 2.0 mM methyl jasmonate for 48 h, 1.5 or 2.0 mM methyl jasmonate for 24 h and 2.0 mM methyl jasmonate for 24 h significantly decreased the viability of T24 cells compared with the control group (P<0.01).

Methyl jasmonate induces the cytotoxicity of human colorectal cancer cells

To confirm that methyl jasmonate induces cytotoxicity in human colorectal cancer cells, an LDH assay was performed to measure the effect of methyl jasmonate on the cytotoxicity of T24 cells. As presented in Fig. 3, treatment with 0.75, 1.5 or 2.0 mM methyl jasmonate induced the cytotoxicity of T24 cells in a dose-dependent manner for 48 h compared with the control group.

Methyl jasmonate induces the apoptosis of human colorectal cancer cells

To elucidate the effect of methyl jasmonate on the induction of apoptosis of human colorectal cancer cells, flow cytometry was performed to analyze the apoptotic rate of T24 cells. As presented in Fig. 4, treatment with 1.5 or 2.0 mM methyl jasmonate significantly induced the apoptosis rate of T24 cell in a dose-dependent manner compared with the control cells (P<0.01).

Methyl jasmonate induces caspase-3 activity in human colorectal cancer cells

Next, the effect of methyl jasmonate on the caspase-3 activity of T24 cells was investigated. As presented in Fig. 5, treatment with 1.5 or 2.0 mM methyl jasmonate significantly induced the caspase-3 activity of T24 cell in a dose-dependent manner compared with the control cells (P<0.01).

Methyl jasmonate downregulates EZH2 expression levels in human colorectal cancer cells

Next, to test the anticancer effect of methyl jasmonate on EZH2 expression in human colorectal cancer cells, the EZH2 protein expression levels in T24 cells was detected using a western blot analysis. As presented in Fig. 6, treatment with 1.5 or 2.0 mM methyl jasmonate significantly downregulated EZH2 protein expression in T24 cell in a dose-dependent manner compared with the control cells (P<0.01).

Methyl jasmonate downregulates Wnt/β-catenin protein expression levels in human colorectal cancer cells

To determine whether methyl jasmonate affected Wnt and β-catenin expression in human colorectal cancer cells, the expression levels of Wnt and β-catenin of T24 cell were detected using western blot analysis. The results of this analysis revealed that Wnt and β-catenin protein expression levels were significantly suppressed by 1.5 or 2.0 mM methyl jasmonate in T24 cells in a dose-dependent manner compared with the control group (P<0.01; Fig. 7).

Downregulation of the expression of EZH2 enhances the anticancer effect of methyl jasmonate on human colorectal cancer cells

To elucidate the mechanism by which apoptosis was induced when cells were treated with methyl jasmonate, the viability of methyl jasmonate-treated T24 cells following the downregulation of the expression of EZH2 was examined. GSK343, an EZH2 inhibitor, significantly suppressed EZH2 protein expression levels in T24 cells compared with cells treated with methyl jasmonate alone (P<0.01) and significantly inhibited the cell viability of T24 cells treated with 2.0 mM methyl jasmonate, compared with the group treated with methyl jasmonate alone (P<0.01; Fig. 8).

Downregulation of the expression of EZH2 enhances the anticancer effect of methyl jasmonate on human colorectal cancer cells through the suppression of Wnt/β-catenin pathway

Next, the effect of the downregulation of the expression of EZH2 on Wnt and β-catenin expression was examined using western blot analysis. Downregulation of the expression of EZH2 significantly suppressed Wnt and β-catenin protein expression in T24 cells treated with 2.0 mM methyl jasmonate, compared with the group treated with methyl jasmonate alone (P<0.01; Fig. 9).

Discussion

In recent years in China, colorectal cancer rates have been gradually increasing, with this increase primarily occurring in large and medium-sized cities (17). According to incomplete statistics, in big cities such as Beijing and Shanghai, the incidence rate by year of colorectal cancer has reached or exceeded the average level in developed Western countries (18). The morbidity rate of colorectal cancer is gradually rising and its malignant biological behavior is closely associated with a small group of tumor stem cells (19). Early-stage diagnosis of colorectal cancer can be missed and in later stages, distant metastasis may occur, together resulting in a poor patient prognosis (20). Therefore, investigations into the molecular mechanism of the occurrence and development of colorectal cancer can aid the prophylaxis and treatment of colorectal tumor types. In the present study, methyl jasmonate significantly suppressed cell growth, inducing cytotoxicity, apoptosis and caspase-3 activity in T24 cells. Zheng et al (13) previously reported that methyl jasmonate abolished the migration, invasion and angiogenesis of gastric cancer cells.

To date, the most insurmountable problems in cancer treatment are the invasion and metastasis of tumors, which results in the mortality of the majority of patients with cancer and is primarily promoted by the migration of tumor cells (21). EZH2 is a transcription inhibition factor that inhibits the transcription of multiple cancer suppressor genes and gives rise to the enhancement of invasion and metastasis; it breaks the balance between the promotion and the inhibition of associated genes by migration, which results in the invasion and metastasis of tumors (22). Abnormally high expression of EZH2 may promote cell proliferation: EZH2 gene expression is markedly increased in multiple tumor types including in the prostate, breast, kidney and lung (8). Therefore, it can be concluded that EZH2 is an oncogene. The present study revealed that methyl jasmonate significantly downregulated EZH2 protein expression in T24 cells in a dose-dependent manner. Wang et al (23) previously reported that methyl jasmonate sensitizes gambogic acid-induced apoptosis of human bladder cancer cells through the downregulation of EZH2 expression by microRNA-101.

The Wnt/β-catenin signaling pathway is highly evolutionarily conserved and controls numerous different events, including human embryonic development, cell fate, tissue and organ morphogenesis, in addition to tumorigenesis (24). Wnt/β-catenin signaling is involved in the development of the central nervous system, reproductive tract, breast, kidney, limbs, placenta, hair and bone (25). The expression imbalance of Wnt/β-catenin pathway constituents may result in embryonic death or abnormal embryonic development (25). There is a close association between the Wnt/β-catenin signaling pathway and tumor development (26). The abnormal activation of the Wnt/β-catenin signaling pathway has been identified in cancer of the breast, liver, stomach, thyroid, lung, prostrate, skin and other malignant tumor types (27). In the present study, it was revealed that the anticancer effect of methyl jasmonate downregulates Wnt/β-catenin expression in human colorectal cancer cells. Raviv et al (28) previously reported that methyl jasmonate downregulated survivin expression and sensitized colon carcinoma cells through the β-catenin pathway.

The present study, to the best of our knowledge for the first time, revealed that the anticancer effect of methyl jasmonate induced apoptosis in human colorectal cancer cells, mediated through the EZH2/Wnt/β-catenin pathway. The findings in the present study suggest that methyl jasmonate may be a potential novel drug for the clinical treatment of human colorectal cancer.

Acknowledgements

Not applicable.

Funding

No funding was received.

Availability of data and materials

The analyzed data sets generated during the study are available from the corresponding author on reasonable request.

Authors' contributions

TTL designed the experiment, analyzed the data and wrote the manuscript. YW, LF, CGC, YKW and TTL performed the experiments.

Ethics approval and consent to participate

Not applicable.

Consent for publication

Not applicable.

Competing interests

The authors declare that they have no competing interests.

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Spandidos Publications style
Wang Y, Fan L, Cui C, Wang Y and Liang T: EZH2 inhibition promotes methyl jasmonate‑induced apoptosis of human colorectal cancer through the Wnt/β‑catenin pathway Retraction in /10.3892/ol.2021.12832. Oncol Lett 16: 1231-1236, 2018
APA
Wang, Y., Fan, L., Cui, C., Wang, Y., & Liang, T. (2018). EZH2 inhibition promotes methyl jasmonate‑induced apoptosis of human colorectal cancer through the Wnt/β‑catenin pathway Retraction in /10.3892/ol.2021.12832. Oncology Letters, 16, 1231-1236. https://doi.org/10.3892/ol.2018.8779
MLA
Wang, Y., Fan, L., Cui, C., Wang, Y., Liang, T."EZH2 inhibition promotes methyl jasmonate‑induced apoptosis of human colorectal cancer through the Wnt/β‑catenin pathway Retraction in /10.3892/ol.2021.12832". Oncology Letters 16.1 (2018): 1231-1236.
Chicago
Wang, Y., Fan, L., Cui, C., Wang, Y., Liang, T."EZH2 inhibition promotes methyl jasmonate‑induced apoptosis of human colorectal cancer through the Wnt/β‑catenin pathway Retraction in /10.3892/ol.2021.12832". Oncology Letters 16, no. 1 (2018): 1231-1236. https://doi.org/10.3892/ol.2018.8779