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 Table of Contents  
ORIGINAL ARTICLE
Year : 2018  |  Volume : 14  |  Issue : 10  |  Page : 609-615

Soybean (Glycine max) prevents the progression of breast cancer cells by downregulating the level of histone demethylase JMJD5


1 Department of Breast Surgery, Affiliated Hospital of Beihua University, Jilin, China
2 Department of Clinical Laboratory, The First Hospital of Jilin University, Changchun, China
3 Department of General Surgery, China-Japan Union Hospital of Jilin University, Changchun, China

Date of Web Publication24-Sep-2018

Correspondence Address:
Haibin Li
Department of Breast Surgery, Affiliated Hospital of Beihua University, No. 12 Jiefang Middle Road, Jilin 132011
China
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Source of Support: None, Conflict of Interest: None


DOI: 10.4103/0973-1482.187292

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 > Abstract 


Background: Breast cancer is the first noticeable disease in female patients. Long-term use of soybean (Glycine max) may prevent the progression of cancer. However, the molecular mechanism for the functions of soybean remains unclear. Histone demethylase JMJD5, an important epigenetic molecule, is overexpressed in the progression of breast cancer suggesting that soybean may ameliorate cancer by affecting the expression of JMJD5.
Materials and Methods: To test the hypothesis, human breast cancer cell lines MCF-7 and MDA-MB-231 were treated with different concentrations of soybean and/or transfected with the plasmids pcDNA3.1-JMJD5 and pTZU6 + 1-shRNA-JMJD5. The growth rate was measured using xCELLigence real-time cell analysis. The level of JMJD5 was measured by using quantitative reverse transcription-polymerase chain reaction and Western blot.
Results: Soybean showed significant inhibitory effects on the growth rates ofMCF-7 and MDA-MB-231 cells in a concentration-dependent way (P < 0.05). Meanwhile, the levels of JMJD5 were reduced with the increase of soybean concentration (P < 0.05). JMJD5 transfection increased the growth rates of MCF-7 and MDA-MB-231 by 25% and 40%. In contrast, the growth rates of MCF-7 and MDA-MB-231 cells were decreased by 17% and 23% after being transfected with JMJD5 shRNA. Soybean inhibited the growth rate of MCF-7 and MDA-MB-231 cells when they were transfected by JMJD5 gene but no for the cells transfected with JMJD5 shRNA.
Conclusion: The complicated compositions of soybean will be beneficial to the therapy of breast cancer since its causes may be involved in multiple aspects. Soybean represses breast cancer development by downregulating the level of JMJD5.

Keywords: Breast cancer, histone demethylase JMJD5, soybean (Glycine max)


How to cite this article:
Wang Y, Liu L, Ji F, Jiang J, Yu Y, Sheng S, Li H. Soybean (Glycine max) prevents the progression of breast cancer cells by downregulating the level of histone demethylase JMJD5. J Can Res Ther 2018;14, Suppl S3:609-15

How to cite this URL:
Wang Y, Liu L, Ji F, Jiang J, Yu Y, Sheng S, Li H. Soybean (Glycine max) prevents the progression of breast cancer cells by downregulating the level of histone demethylase JMJD5. J Can Res Ther [serial online] 2018 [cited 2019 Sep 21];14:609-15. Available from: http://www.cancerjournal.net/text.asp?2018/14/10/609/187292




 > Introduction Top


Breast cancer is the most common malignant and the second leading cause of cancer-related mortality in women worldwide.[1] The management of breast cancer is a big challenge for the most researchers. The main reason is that various mechanisms are involved in the development of breast cancer[2],[3],[4],[5] and no effective drug can be used clinically for preventing the progression of breast cancer. Radiochemotherapy is still a main way for the therapy of breast cancer, but the therapy will cause significant side effects.[6]

Soybean (Glycine max) has rich essential amino acids[7],[8] and been reported to prevent the progression of breast cancer.[9],[10] On the other hand, soybeans can be used as food with fewer side effects. However, the molecular mechanism for soybeans controlling the development of breast cancer remains widely unknown. Development of breast cancer may be caused by the changes of many different genes, which affect the structure and function of patients at the genome levels. The changes of DNA copy, messenger RNA (mRNA), and microRNA expression can also result in the deregulation of biological pathways in cancer development.[11] Epigenetic regulation of some genes or RNAs has been approved to be associated with the risk of various cancers.[12] Histone methylation plays an important role in the epigenetic control of many biological actives, such as immunological responses and cellular aging.[13] JMJD5 is a member of the Jumonji C domain-containing demethylase family, which demethylates H3K36me2[14] and is involved in a cell cycle.[15],[16] JMJD5 can interact with pyruvate kinase muscle isozyme to control metabolic flux in carcinoma tissues.[17] Recent work showed that JMJD5 influences cell migration, invasion, and malignant status of breast cancer.[18] Therefore, we explored the effects of soybean on breast cancer line cells by investigating the changing levels of JMJD5 with soybean treatment.


 > Materials and Methods Top


Analysis of soybean (Glycine max)

Soybean was purchased from local suppliers. The ingredient of soybean was analyzed using the following protocols: 10 g soybean seeds were ground into powder by using a mortar and pestle. Oil was isolated by the addition of hexanes and incubated at 45°C for 1 h. The supernatant was collected and dried at 80°C for 48 h. Lipid profile was analyzed by a gas chromatography (GC-950, Shanghai Haixin Chromatographic Instruments Co., Shanghai, China). The precipitation was used for the analysis of protein and starch. The soluble protein was precipitated by using trichloroacetic acid and measured based on a Micro-Kjeldahl method.[19] Starch was solubilized in water at 100°C and treated with amyloglucosidase according to a method previously described.[20] The glucose contents were analyzed by hexokinase/glucose-6-phosphate dehydrogenase.[21] Trace elements were measured according to a previous report.[22] Moisture, ash, and other contents were measured by using official methods of the Association of Official Analytical Chemists.[23]

pcDNA3.1-JMJD5 reconstruction

JMJD5 gene (accession number: BC027911.1) was amplified using the primers (sense primer, 5′-GTGAGCTAGCatggctggagacacccactg-3′; antisense primer, 5′-CTGAGAATTCctacgaccaccagaagctgac-3′) producing about 1260-bp products. The final polymerase chain reaction (PCR) fragments were linked with pcDNA3.1 vector (Applied Biosystems China Limited, Beijing, China) at the sites of NheI-EcoRI and constructed the plasmid pcDNA3.1-JMJD5. The reconstructed plasmid was amplified in  Escherichia More Details coli, and isolated by using a QIAprep Miniprep Kit (Qiagen, Beijing, China). Finally, the sequence was verified by DNA sequencing.

Constructs for JMJD5 shRNA

The pTZU6 + 1 expression plasmid was a gift from the Hepatitis Institute of Chongqing Medical University (Chongqing, China). JMJD5 coding sequence and the reverse complementary sequence were synthesized: siJMJD5, sense 5′-TCGACGGAGTTTGGAGTATATCCAGGAGATTT GGATCTCCTGGATATACTCCAAACTCCTTTTTT-3′; antisense 5′-CTAGAAAAAAGTTTGGAGTATATCCAGGAGATCCAAATCTCCT GGATATACTCCAAACTCCGG-3′. SalI and XbaI restriction sites were linked to the either end of the oligos and constructed the vector pTZU6 + 1-shRNA-JMJD5.

Transfection of MCF-7 and MDA-MB-231 cells

Human breast cancer line cells MCF-7 and MDA-MB-231 were purchased from the Cell Bank of Chinese Academy of Sciences (Shanghai, China). MCF-7 cells were transfected with 2 μg of pcDNA3.1-JMJD5 and/or pTZU6+1-shRNA-JMJD5. Transfection was conducted by using 10 μl of lipofectamine 2000TM (Thermo Fisher Scientific, Waltham, MA, USA) when the cells reached 50% confluence in plates. At the 2nd day after transfection, all the antibiotics-resistant cells were selected by using 500 μg/ml G-418. Resistant colonies were further cultured at the same condition after isolation.

Effects of soybean on MCF-7 and MDA-MB-231 cells

The effects of soybean on MCF-7 and MDA-MB-231 cells were identified by measuring the growth rate of cells by adding different concentrations of soybean. MCF-7 and MDA-MB-231 cell lines were cultured in RPMI medium 1640 at 37°C and 5% CO2. Cells were subcultured every 48 h and collected. Then, the cells were adjusted to a concentration of 1 × 105 cells/ml in each cell and incubated with different concentrations of soybean (0, 0.5, 1, 1.5, and 2 mg/ml) for 24 h. The transfected cells were treated with 2 mg/ml soybean for 24 h. The growth rate was measured in E-plate 96 by an xCELLigence-system (Roche Applied Science, Indianapolis, IN, USA).

Real-time quantitative reverse transcription polymerase chain reaction

The levels of JMJD5 were measured using quantitative reverse transcription PCR (qRT-PCR). qRT-PCR was performed using SYBR Green qPCR Master Mixes from SABiosciences (Frederick, MD, USA). RNA was extracted from MCF-7 and MDA-MB-231 cell lines using TaKaRa MiniBEST Universal RNA Extraction Kit from TaKaRa Bio Inc., (Dalian, China). Complementary DNA (cDNA) was synthesized using purified RNA and PrimeScript 1st strand cDNA Synthesis Kit from TaKaRa Bio Inc., (Dalian, China). PCR primers for JMJD5 gene were: forward primer, 5'-agggacgagtgtctgcagag-3' and reverse primer, 5'-cacagacacagggctttcag-3'; β-actin, forward primer 5'-gtggcatccacgaaactaca-3' and reverse primer, 5'-agtgatctccttctgcatcc-3'.

Western blotting

All the proteins were separated by sodium dodecyl sulfate-polyacrylamide gel electrophoresis and transferred to a polyvinylidene difluoride membrane (Millipore, MA, USA). The membrane was treated with 5% skim milk in TBST buffer, anti-JMJD5 antibody (Cat. No., ab36104, 1:3000 dilutions), and anti-beta-actin (ab8227) from Abcam Inc., (Cambridge, MA, USA) overnight at 4°C. Subsequently, the membrane was incubated with horseradish peroxidase-conjugated secondary antibody (Cat. No., ab6721, Abcam Inc., Cambridge, MA, USA).

Statistical analysis

All results were presented as mean values ± standard deviation SPSS version 20.0 software (SPSS Inc. Chicago, ILL, USA) was used to analyze these data. A t-test was conducted to compare the data before and after receiving soybean treatment.


 > Results Top


The complicated compositions of soybean will be beneficial to the therapy of breast cancer

As [Table 1] indicated, there are about 35.3 ± 1.9% and 11.5 ± 0.5% of protein and fatty acid in soybeans based on its weight [Table 1]. Soybean has rich proteins and may inhibit the growth of MCF-7 and MDA-MB-231 by the multiple functions of soybean. For other compositions, there are 31.6 ± 1.4% carbohydrate, 8.2 ± 0.4% fiber, 4.2 ± 0.3% ash, and about 1% race elements. Furthermore, the main soluble carbohydrates of soybeans are sucrose, raffinose, and stachyose.[24] Thus, the complicated compositions of soybean will be beneficial to the therapy of breast cancer.
Table 1: The composition of soybean (10 g)

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The effects of soybean on MCF-7 and MDA-MB-231 cells

In this study, the detection for real-time cell growth was used to test the effects of soybean onMCF-7 and MDA-MB-231 cells. As showed in [Figure 1]a and [Figure 1]c, soybean has strong inhibitory effects on human breast cancer cell lines MCF-7 and MDA-MB-231. The growth rates of all the cells were affected by soybean in a concentration-dependent way. There were significantly statistical differences for the growth rate of all cells between a control group and a soybean-treated group when the concentration was more than 1 mg/ml (P < 0.05). All the results suggest that different concentration soybean has different inhibitory effects on the grow rate of MCF-7 and MDA-MB-231, and the soybean may be new functional food for treating human breast cancer. On the other hand, the growth rated increased by 25% and 40%, respectively, when the cells were transfected by pcDNA3.1-JMJD5. In contrast, the growth rate reduced by 17% and 23%, respectively, when the cells were transfected by JMJD5 shRNA [Figure 1]b and [Figure 1]d. Furthermore, 2 mg/ml soybean showed significant inhibitory activities for the growth rate of the MCF-7 and MDA-MB-231 cells transfected with JMJD5 (P < 0.05) but no such activities for the cells transfected with JMJD5 shRNA (P > 0.05) [Figure 1]b and [Figure 1]d.
Figure 1: Real-time analysis for the effects of soybean on the growth rate of MCF-7 and MDA-MB-231 cells. (a) The effects of different dosages of soybean on the growth rate of MCF-7. (b) The effects of JMJD5 on the growth rate of MCF-7. (c) The effects of different dosages of soybean on the growth rate of MDA-MB-231 cells. (d) The effects of JMJD5 on the growth rate of MDA-MB-231 cells. Control, MCF-7, and MDA-MB-231 cells were not transfected with any gene. All the cells can be divided into six groups according to different treatments: control, control + COS, JMJD5, JMJD5 + COS, JMJD5 shRNA and JMJD5 shRNA + COS groups. Control + COS, MCF-7, and MDA-MB-231 cells were treated with 2 mg/ml COS. JMJD5, the cells were transfected with pcDNA-3.1-JMJD5. JMJD5 + COS, the cells were transfected with pcDNA-3.1-JMJD5 and treated with 2 mg/ml COS. JMJD5 shRNA, the cells were transfected with the vector pTZU6+1-shRNA-JMJD5. JMJD5 shRNA + COS, the cells were transfected with the vector pTZU6+1-shRNA-JMJD5 and treated with 2 mg/ml COS. JMJD5 shRNA. The cell growth rates were calculated as the mean values of three independent experiments and presented as mean values ± standard deviation. All the cells were cultured for 24 h

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Soybean reduces the messenger RNA levels of JMJD5

qRT-PCR analysis showed that the mRNA levels of JMJD5 were same among all groups before the treatment (P > 0.05). The low levels of JMJD5 mRNA could be detected in a soybean group after 1-day culture (P < 0.05). The levels of JMJD5 mRNA were reduced significantly when the concentration of soybean was more than 1 mg/ml (P < 0.05) [Figure 2]a and [Figure 2]c. [Figure 2]b and [Figure 2]d showed that the mRNA levels of JMJD5 significantly increased when the cells were transfected with pcDNA3.1-JMJD5 (P < 0.05) [Figure 2]b and [Figure 2]d. In contrast, the mRNA levels of JMJD5 significantly reduced when the cells were transfected with JMJD5 shRNA (P < 0.05) [Figure 2]b and [Figure 2]d. The results suggested that the cells were successfully transfected by pcDNA3.1-JMJD5 and pTZU6+1-shRNA-JMJD5. Furthermore, 2 mg/ml soybean showed significant inhibitory activities for the mRNA levels of the MCF-7 and MDA-MB-231 cells transfected with JMJD5 (P < 0.05) but no such activities for the cells transfected with JMJD5 shRNA (P > 0.05) [Figure 2]b and [Figure 2]d.
Figure 2: Quantitative reverse transcription-polymerase chain reaction analysis of the relative messenger RNA levels of JMJD5 in MCF-7 and MDA-MB-231 cells. (a) The effects of different concentration of soybean on relative messenger RNA levels of JMJD5 in MCF-7 cells. (b) Relative messenger RNA levels of JMJD5 in the transfected or nontransfected MCF-7 cells. (c) The effects of different concentration of soybean on the relative messenger RNA levels of JMJD5 in MDA-MB-231 cells. (d) The relative messenger RNA levels of JMJD5 in the transfected or nontransfected MDA-MB-231 cells. Control, MCF-7, and MDA-MB-231 cells were not transfected with any gene. Control + COS, MCF-7, and MDA-MB-231 cells were treated with 2 mg/ml COS. JMJD5, the cells were transfected with pcDNA-3.1-JMJD5. JMJD5 + COS, the cells were transfected with pcDNA-3.1-JMJD5 and treated with 2 mg/ml COS. JMJD5 shRNA, the cells were transfected with the vector pTZU6+1-shRNA-JMJD5. JMJD5 shRNA + COS, the cells were transfected with the vector pTZU6+1-shRNA-JMJD5 and treated with 2 mg/ml COS. JMJD5 shRNA. Each bar was presented as the mean ± standard deviation of three independent experiments. *P < 0.05 via a control group. #P < 0.05 via the control without the addition of soybean peptides

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Soybean represses breast cancer development by downregulating the level of JMJD5

Western blot showed that the protein levels of JMJD5 were also same among all groups before the treatment (P > 0.05). The low protein levels of JMJD5 could be detected in a soybean group after 1-day culture (P < 0.05). The levels of JMJD5 mRNA were significantly reduced when the soybean reached more than 1 mg/ml [Figure 3]a and [Figure 3]c. Just like the results from qRT-PCR analysis, the results suggested that soybean treatment inhibits the protein levels of JMJD5. All these results suggested that soybean can reduce the levels of JMJD5 in a dosage-dependent manner. [Figure 3]b and [Figure 3]d showed that the protein levels of JMJD5 significantly increased when the cells were transfected with pcDNA3.1-JMJD5 (P < 0.05). In contrast, the protein levels of JMJD5 significantly reduced when the cells were transfected with JMJD5 shRNA (P < 0.05) [Figure 3]b and [Figure 3]d. Thus, the results also suggested that the cells were successfully transfected by pcDNA3.1-JMJD5 and pTZU6 + 1-shRNA-JMJD5. Furthermore, 2 mg/ml soybean showed significant inhibitory activities for the protein levels of the MCF-7 and MDA-MB-231 cells transfected with JMJD5 (P < 0.05) but no such activities for the cells transfected with JMJD5 shRNA (P > 0.05) [Figure 3]b and [Figure 3]d.
Figure 3: Western blot analysis for the relative protein levels of JMJD5 in MCF-7 and MDA-MB-231 cells. (a) The effects of different concentration of soybean on relative protein levels of JMJD5 in MCF-7 cells. (b) Relative protein levels of JMJD5 in the transfected or nontransfected MCF-7 cells. (c) The effects of different concentration of soybean on protein levels of JMJD5 in MDA-MB-231 cells. (d) The relative protein levels of JMJD5 in the transfected or nontransfected MDA-MB-231 cells. Control, MCF-7, and MDA-MB-231 cells were not transfected with any gene. Control + COS, MCF-7, and MDA-MB-231 cells were treated with 2 mg/ml COS. JMJD5, the cells were transfected with pcDNA-3.1-JMJD5. JMJD5 + COS, the cells were transfected with pcDNA-3.1-JMJD5 and treated with 2 mg/ml COS. JMJD5 shRNA, the cells were transfected with the vector pTZU6+1-shRNA-JMJD5. JMJD5 shRNA + COS, the cells were transfected with the vector pTZU6+1-shRNA-JMJD5 and treated with 2 mg/ml COS. JMJD5 shRNA. Each bar was presented as the mean values ± standard deviation of three independent experiments. *P < 0.05 via a control group. #P < 0.05 via the control without the addition of soybean peptides

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 > Discussion Top


Breast cancer is the most common disease among women in the world, and more than 1 million new cases of breast cancer can be diagnosed each year.[25] It is critical to find an effective way to treat breast cancer with fewer side effects. The multiple beneficial functions of soybeans have received much attention because soybean can promote human healthy situation.[26] Soybean milk has been fermented through lactic acid bacteria and used to prepare bean-curd, cheese-like, and yogurt-type products.[27] In China, bean curd and soybean milk have been widel consumed. Breast cancer has been the leading cause of death among women. Soybean has also been reported to have anticancer activities[28] and reduce the incidence of breast cancer.[29] Previous work showed that the protective role of protease inhibitors, such as the Bowman–Birk inhibitor and Kunitz-trypsin inhibitor in soybean, are responsible for the antiproliferative activity against colon cancer.[30]

qRT-PCR and Western blot analysis showed that soybean inhibits the level of JMJD5 in a concentration-dependent way (P < 0.05) [Figure 2]a, [Figure 2]c, and [Figure 3]a, [Figure 3]c. Furthermore, 2 mg/ml soybean inhibited the level of JMJD5 in 7MCF-7 and MDA-MB-231 cells transfected with JMJD5 but not in the cells transfected with JMJD5 shRNA [Figure 2]b, [Figure 2]d and [Figure 3]b, [Figure 3]d. The results suggest that soybean showed the effects on breast cancer cells through regulating the level of JMJD5. On the other hand, the overexpression of JMJD5 promotes the growth of MCF-7 and MDA-MB-231 while JMJD5 silence inhibits the growth of MCF-7 and MDA-MB-231 (P < 0.05) [Figure 1]a. All the result also implied that the inhibitory activities of soybean on JMJD5 contribute to preventing the progression of breast cancer cells. Soybean can also be developed as a kind of functional food for the therapy of breast cancer by down-regulating the JMJD5. Dietary soybean, as a kind of functional food, provides a therapeutic approach to control the development of breast cancer.

Soybean can inhibit the progression of breast cancer cells and may be beneficial for many reasons. First, soybean has rich proteins, which may be associated with the inhibitory functions in the development of breast cancer cells since most breast cancer resistant proteins have been reported.[31],[32],[33],[34],[35] For example, soy proteins have breast tumor suppressing activity. Previous work suggested that soy protein can inhibit the progression of breast tumor development by inhibiting the expression of some tumor-related genes, such as peripheral benzodiazepine receptors.[36] Soy may have the constituents protecting against breast cancer and been investigated clinically. The results showed that soy food intake is related with a reduced risk of breast cancer and its effects are more pronounced in premenopausal women.[37] Second, soybean has more than 7% linoleic acid according to dry weight ratio [Table 1]. Meta-analysis showed that linoleic acid intake is associated with reduced risk of breast cancer. However, no association is statistically significant and further work needs to be done to confirm the conclusion.[38] Other work indicated that the major conjugated linoleic acid isomers have inhibitory functions on breast cancer by mediating the intercellular gap junction communication through the upregulation of Cx43 expression and the inactivation of nuclear factor-kappa B, and the production of reactive of species in breast cancer cells.[39] Finally, soybean has rich fibers for more than 8% of its weight [Table 1] while fiber intake was stringently associated with the incidences of breast cancer.[40] In any case, considering the complicated causes of breast cancer, the multiple inhibitory functions of soybean may be beneficial from its complex components.

Certainly, there are some limitations for the present work. Although soybean has been widely used as functional food in China, the molecular mechanisms for its multiple functions remain unclear. Here, more functions of soybean will be analyzed using more advanced biochemical methodology and animal models. More importantly, some contrary results for the inhibitory effects of soybean on breast cancer still exist. For example, BRF2 is a transcription factor and the overexpression of BRF2 can transform human mammary epithelial cells. In breast and lung cancers, the BRF2 gene is overexpressed and may serve as an oncogenic driver. Dietary isoflavones from soybean can induce BRF2 in female animals, whereas the converse occurs in male animals.[41] Therefore, much work needs to be done in the future.

Soybean has promising effects on breast cancer, promoting mental health and vitality by downregulating the levels of JMJD5. Although the detail mechanism of soybean on breast cancer remains unknown, it seems that soybean is promising by preventing the development of breast cancer cells. Soybean should be developed as a potential food for the therapy of breast cancer since no single effective drug has been created.

Financial support and sponsorship

Nil.

Conflicts of interest

There are no conflicts of interest.



 
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