Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms
Abstract
:1. Introduction
2. Materials and Methods
2.1. Animals
2.2. Animal Diets
2.3. Tumor Implantation, Observation, and Collection
2.4. RNA Sequencing (RNA-Seq) Analysis
2.5. Differentially Expressed Gene (DEG) Analysis
2.6. Gene Set Function Enrichment
2.7. Quantitative Real-Time PCR
2.8. Western Blot Analysis
2.9. DNA Methyltransferase (DNMT) and Histone Deacetylase (HDAC) Activity Assay
2.10. Global DNA Methylation, Hydroxymethylation and Histone Methylation Analysis
2.11. Statistical Analysis
3. Results
3.1. Dietary GE Inhibited TNBC Growth in PDX Models
3.2. Genome-Wide Transcriptomic Alterations Induced by GE Administration in BCM-3204 PDX Model
3.3. Validation Analyses of Target Gene Expression at Transcriptional and Translational Levels
3.4. Cd74-Regulated Signaling Pathway May Contribute to GE Diet-Induced Therapeutic Effects against TNBC
3.5. Dietary GE Treatment Resulted in Expression Changes in Multiple Epigenetic-Related Genes
3.6. GE Influenced Global Epigenetic Profiles
4. Discussion
Supplementary Materials
Author Contributions
Funding
Institutional Review Board Statement
Data Availability Statement
Acknowledgments
Conflicts of Interest
Abbreviations
Cd74 | Cluster of Differentiation 74 |
cDNA | Complementary DNA |
DEGs | Differentially expressed genes |
Dnmts | DNA methytransferases |
ER | Estrogen receptor |
FastQC | FastQ quality control |
FC | Fold change |
FDR | False-discovery rate |
Fzd9 | Frizzled 9 |
GE | Genistein |
GO | Gene Ontology |
Hdac | Histone deacetylase |
HER-2 | Human epidermal growth factor receptor 2 |
hTERT | Human telomerase reverse transcriptase |
Ifi44 | Interferon-Induced Protein 44 |
Lpl | Lipoprotein lipase |
NF-κB | Nuclear factor kappa B |
NOD | Nonobese diabetic |
NSG | NOD/SCID/IL-2γ-receptor null |
PCoA | Principal Coordinates Analysis |
PDX | Patient-derived xenograft |
PR | Progesterone receptor |
RNA-seq | RNA sequencing |
Sat1 | Spermidine/spermine-N1-acetyltransferase 1 |
TAp63 | Tumor protein p63 |
Tet | Ten-eleven translocation |
TNBC | Triple negative breast cancer |
Wwc1 | WW and C2 domain containing 1 |
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Gene Symbol | Gene Expression Fold Change (log2FC) | Average Differential Expression | p-Value for Differential Expression | False Discovery Rate (FDR) |
---|---|---|---|---|
Cd74 | −4.760 | 2.879 | 2.20 × 10−7 | 0.003 |
Lpl | −2.806 | 2.294 | 2.26 × 10−6 | 0.017 |
Ifi44 | −2.191 | 2.100 | 8.23 × 10−6 | 0.027 |
Dnah6 | −6.634 | −3.412 | 5.63 × 10−6 | 0.027 |
Il20rb | 6.115 | −3.578 | 9.12 × 10−6 | 0.027 |
Wwc1 | 0.903 | 5.994 | 1.27 × 10−5 | 0.028 |
Sat1 | −0.823 | 6.315 | 1.49 × 10−5 | 0.028 |
Al139300.1 | 5.984 | −3.559 | 1.32 × 10−5 | 0.028 |
Akt3 | 1.335 | 5.583 | 2.34 × 10−5 | 0.037 |
Ipo5 | 0.935 | 7.051 | 2.46 × 10−5 | 0.037 |
Gda | −1.759 | 2.098 | 3.27 × 10−5 | 0.039 |
Fzd9 | −1.186 | 4.141 | 4.89 × 10−5 | 0.039 |
Cdk6 | 0.903 | 9.485 | 4.07 × 10−5 | 0.039 |
Hla-dqa1 | −5.147 | −1.468 | 4.60 × 10−5 | 0.039 |
Adgrf2 | −4.405 | −3.498 | 3.85 × 10−5 | 0.039 |
Page5 | 4.595 | −3.685 | 3.63 × 10−5 | 0.039 |
Fam236b | −4.509 | −3.722 | 4.96 × 10−5 | 0.039 |
Ac053503.6 | 4.624 | −3.537 | 5.12 × 10−5 | 0.039 |
Csf1r | 5.257 | −3.778 | 3.26 × 10−5 | 0.039 |
Nt5c1b-rdh14 | −4.914 | −3.895 | 5.25 × 10−5 | 0.039 |
Gene | Function in Cancer | Epigenetic Regulation | RNA-Seq |
---|---|---|---|
Cluster of Differentiation 74 (Cd74) | Cd74 is overexpressed in breast cancer patients. It is also found to be significantly correlated with lymph node metastasis in TNBC [38] | Epigenetic mechanisms play a role in Cd74 expression via Cd74 promoter methylation [39] | DEG, significant decrease (4.76 fold) |
Lipoprotein lipase (Lpl) | Breast cancer and sarcoma cells express and secrete active Lpl enzyme to acquire fatty acids from the blood circulation, which facilitate growth of these cells [40] | Epigenetic changes at the promoter regions may alter expression of the Lpl gene and may play an important role in prostate cancer development [41] | DEG, significant decrease (2.8 fold) |
Frizzled 9 (Fzd9) | Oncogene. Overexpressed Fzd9 is found in various types of cancer [42,43] | Hypermethylated Fzd9 is associated with hormone receptor positive, luminal A, or p53 wild-type breast cancers [44] | DEG, significant decrease (1.18 fold) |
Spermidine/spermine-N1-acetyltransferase 1 (Sat1) | Sat1 overexpression is correlated with poor clinical outcomes [45] | Sat1 is involved in acetylation of histone H3, resulting in chromatin remodeling and regulation of gene expression [45] | DEG, significant decrease (0.82 fold) |
Interferon-Induced Protein 44 (Ifi44) | Oncogene. Overexpressed Ifi44 is found in head and neck squamous cell carcinoma and functioned heterogeneously in tumor formation and progression [46] | Iifi44 promoter hypomethylation can distinguish systemic lupus erythematosus patients from healthy persons, promising to be first novel epigenetic diagnostic marker [47] | DEG, significant decrease (2.19 fold) |
WW and C2 domain containing 1 (Wwc1) | Tumor-suppressor gene. Low Wwc1 expression is associated with aggressive breast cancer and poor survival outcomes [48] | DNA methylation is negatively correlated with Wwc1 expression [48] | DEG, significant increase (0.90 fold) |
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Sharma, M.; Arora, I.; Chen, M.; Wu, H.; Crowley, M.R.; Tollefsbol, T.O.; Li, Y. Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms. Nutrients 2021, 13, 3944. https://doi.org/10.3390/nu13113944
Sharma M, Arora I, Chen M, Wu H, Crowley MR, Tollefsbol TO, Li Y. Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms. Nutrients. 2021; 13(11):3944. https://doi.org/10.3390/nu13113944
Chicago/Turabian StyleSharma, Manvi, Itika Arora, Min Chen, Huixin Wu, Michael R. Crowley, Trygve O. Tollefsbol, and Yuanyuan Li. 2021. "Therapeutic Effects of Dietary Soybean Genistein on Triple-Negative Breast Cancer via Regulation of Epigenetic Mechanisms" Nutrients 13, no. 11: 3944. https://doi.org/10.3390/nu13113944