Investigation of DNMT-mediated DNA methylation and its role in adipogenesis and breast cancer
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Abstract
DNA methylation, which is mediated by DNMTs, plays crucial roles in regulating gene expression and cell differentiation. In this study, we identified adipogenesis-related genes and analyzed their coexpression with DNMT isoforms in breast cancer samples from the TCGA dataset. Our findings revealed that 114 genes were coexpressed with DNMTs, among which six genes, GATA3, IRS1, LPIN1, ME3, SREBF1, and STAT1, were significantly negatively correlated with methylation and expression levels, as determined using Spearman correlation with false discovery rate correction to account for multiple testing. The differential expression patterns of these genes across breast cancer subtypes and their associations with survival outcomes were examined. Specifically, ME3 and STAT1 showed distinct associations with survival outcomes, where high ME3 expression correlated with significantly better survival rates, whereas low STAT1 expression was associated with improved prognosis. ME3 expression was significantly elevated in tumors with high adipocyte enrichment, particularly in the luminal B subtype, suggesting a subtype-specific relationship between adipogenesis and tumor behavior. Conversely, STAT1 exhibited lower expression in samples with high adipocyte counts, reinforcing its role in the tumor microenvironment. These results underscore the importance of DNMT-mediated DNA methylation in adipogenesis and breast cancer.
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Mallya, S., Bhat, S. M., Naie , S., Kulkarni , S., Joshi, M. B., Kabekkodu, S. P., & Chakrabarty, S. (2025). Investigation of DNMT-mediated DNA methylation and its role in adipogenesis and breast cancer. Communications in Science and Technology, 10(1), 201-208. https://doi.org/10.21924/cst.10.1.2025.1678
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L. García-Estévez, J. Cortés, S. Pérez, I. Calvo, I. Gallegos, and G. Moreno-Bueno, Obesity and Breast Cancer: A Paradoxical and Controversial Relationship Influenced by Menopausal Status, Front. Oncol. 11 (2021) 705911.
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C. Blucher and S.C. Stadler, Obesity and Breast Cancer: Current Insights on the Role of Fatty Acids and Lipid Metabolism in Promoting Breast Cancer Growth and Progression, Front. Endocrinol. 8 (2017) 293.
I. Rybinska, N. Mangano, E. Tagliabue, and T. Triulzi, Cancer-Associated Adipocytes in Breast Cancer: Causes and Consequences, Int. J. Mol. Sci. 22 (2021) 3775.
B. Dirat, L. Bochet, M. Dabek, D. Daviaud, S. Dauvillier, B. Majed, et al., Cancer-Associated Adipocytes Exhibit an Activated Phenotype and Contribute to Breast Cancer Invasion, Cancer Res. 71 (2011) 2455–2465.
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Y.J. Cha and J.S. Koo, Adipokines as therapeutic targets in breast cancer treatment, Expert Opin. Ther. Targets 22 (2018) 941–953.
Y. Gao, X. Chen, Q. He, R.C. Gimple, Y. Liao, L. Wang, et al., Adipocytes promote breast tumorigenesis through TAZ-dependent secretion of Resistin, Proc. Natl. Acad. Sci. 117 (2020) 33295–33304.
J. Choi, Y.J. Cha, and J.S. Koo, Adipocyte biology in breast cancer: From silent bystander to active facilitator, Prog. Lipid Res. 69 (2018) 11–20.
F. Zhang and S. Liu, Mechanistic insights of adipocyte metabolism in regulating breast cancer progression, Pharmacol. Res. 155 (2020) 104741.
T. Masuda, H. Fujimoto, R. Teranaka, M. Kuroda, Y. Aoyagi, T. Nagashima, et al., Anti-HER2 antibody therapy using gene-transduced adipocytes for HER2-positive breast cancer, Breast Cancer Res. Treat. 180 (2020) 625–634.
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H. Ogata, S. Goto, K. Sato, W. Fujibuchi, H. Bono, and M. Kanehisa, KEGG: Kyoto Encyclopedia of Genes and Genomes, Nucleic Acids Res. 27 (1999) 29–34.
M. Uhlen, L. Fagerberg, B.M. Hallstrom, C. Lindskog, P. Oksvold, A. Mardinoglu, et al., Tissue-based map of the human proteome, Science 347 (2015) 1260419.
A. Agrawal, H. Balc?, K. Hanspers, S.L. Coort, M. Martens, D.N. Slenter, et al., WikiPathways 2024: next generation pathway database, Nucleic Acids Res. 52 (2024) D679–D689.
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A.R. Quinlan and I.M. Hall, BEDTools: a flexible suite of utilities for comparing genomic features, Bioinformatics 26 (2010) 841–842.
E. Cerami, J. Gao, U. Dogrusoz, B.E. Gross, S.O. Sumer, B.A. Aksoy, et al., The cBio Cancer Genomics Portal: An Open Platform for Exploring Multidimensional Cancer Genomics Data, Cancer Discov. 2 (2012) 401–404.
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D. Aran, Z. Hu, and A.J. Butte, xCell: digitally portraying the tissue cellular heterogeneity landscape, Genome Biol. 18 (2017) 220.
L.A. Al-Kharashi, F.H. Al-Mohanna, A. Tulbah, and A. Aboussekhra, The DNA methyl-transferase protein DNMT1 enhances tumor-promoting properties of breast stromal fibroblasts, Oncotarget 9 (2017) 2329–2343.
H. Liu, Y. Song, H. Qiu, Y. Liu, K. Luo, Y. Yi, et al., Downregulation of FOXO3a by DNMT1 promotes breast cancer stem cell properties and tumorigenesis, Cell Death Differ. 27 (2020) 966–983.
Y. He, Q. Hu, L. Wang, and C. Chen, Decitabine/paclitaxel co-delivery systems modified with anti-PD-L1 antibodies mediate chemoimmunotherapy for Triple negative breast cancer, Mater. Des. 237 (2024) 112562.
P. Yadav, S. Bandyopadhayaya, S. Soni, S. Saini, L.K. Sharma, S.K. Shrivastava, et al., Simvastatin prevents BMP-2 driven cell migration and invasion by suppressing oncogenic DNMT1 expression in breast cancer cells, Gene 882 (2023) 147636.
J.D. Roll, A.G. Rivenbark, W.D. Jones, and W.B. Coleman, DNMT3b overexpression contributes to a hypermethylator phenotype in human breast cancer cell lines, Mol. Cancer 7 (2008) 15.
D.T. Butcher and D.I. Rodenhiser, Epigenetic inactivation of BRCA1 is associated with aberrant expression of CTCF and DNA methyltransferase (DNMT3B) in some sporadic breast tumours, Eur. J. Cancer 43 (2007) 210–219.
H. Xie, X. Liu, Q. Zhou, T. Huang, L. Zhang, J. Gao, et al., DNA Methylation Modulates Aging Process in Adipocytes, Aging Dis. 13 (2022) 433–446.
Y.J. Park, S. Lee, S. Lim, H. Nahmgoong, Y. Ji, J.Y. Huh, et al., DNMT1 maintains metabolic fitness of adipocytes through acting as an epigenetic safeguard of mitochondrial dynamics, Proc. Natl. Acad. Sci. 118 (2021) e2021073118.
D. You, E. Nilsson, D.E. Tenen, A. Lyubetskaya, J.C. Lo, R. Jiang, et al., Dnmt3a is an epigenetic mediator of adipose insulin resistance, eLife 6 (2017) e30766.
A.Y. Kim, Y.J. Park, X. Pan, K.C. Shin, S.-H. Kwak, A.F. Bassas, et al., Obesity-induced DNA hypermethylation of the adiponectin gene mediates insulin resistance, Nat. Commun. 6 (2015) 7585.
Y.C. Lim, S.Y. Chia, S. Jin, W. Han, C. Ding, and L. Sun, Dynamic DNA methylation landscape defines brown and white cell specificity during adipogenesis, Mol. Metab. 5 (2016) 1033–1041.
Y. Huang, Y. Yang, X. Chen, S. Zeng, Y. Chen, H. Wang, et al., Downregulation of malic enzyme 3 facilitates progression of gastric carcinoma via regulating intracellular oxidative stress and hypoxia-inducible factor-1? stabilization, Cell. Mol. Life Sci. 81 (2024) 375.
Y. Zhang and Z. Liu, STAT1 in Cancer: Friend or Foe?, Discov. Med. 24 (2017) 19–29.
T.A.J. Grell, M. Mason, A.A. Thompson, J.C. Gómez-Tamayo, D. Riley, M.V. Wagner, et al., Integrative structural and functional analysis of human malic enzyme 3: A potential therapeutic target for pancreatic cancer, Heliyon 8 (2022) e12392.
S.P. Totten, Y.K. Im, E. Cepeda Cañedo, O. Najyb, A. Nguyen, S. Hébert, et al., STAT1 potentiates oxidative stress revealing a targetable vulnerability that increases phenformin efficacy in breast cancer, Nat. Commun. 12 (2021) 3299.
S. Varikuti, S. Oghumu, M. Elbaz, G. Volpedo, D.K. Ahirwar, P.C. Alarcon, et al., STAT1 gene deficient mice develop accelerated breast cancer growth and metastasis which is reduced by IL-17 blockade, OncoImmunology 6 (2017) e1361088.
V.R. Zellmer, P.M. Schnepp, S.L. Fracci, X. Tan, E.N. Howe, and S. Zhang, Tumor-induced Stromal STAT1 Accelerates Breast Cancer via Deregulating Tissue Homeostasis, Mol. Cancer Res. 15 (2017) 585–597.
I. Rybinska, N. Mangano, E. Tagliabue, and T. Triulzi, Cancer-Associated Adipocytes in Breast Cancer: Causes and Consequences, Int. J. Mol. Sci. 22 (2021) 3775.
B. Dirat, L. Bochet, M. Dabek, D. Daviaud, S. Dauvillier, B. Majed, et al., Cancer-Associated Adipocytes Exhibit an Activated Phenotype and Contribute to Breast Cancer Invasion, Cancer Res. 71 (2011) 2455–2465.
L. Lapeire, A. Hendrix, K. Lambein, M. Van Bockstal, G. Braems, R. Van Den Broecke, et al., Cancer-Associated Adipose Tissue Promotes Breast Cancer Progression by Paracrine Oncostatin M and Jak/STAT3 Signaling, Cancer Res. 74 (2014) 6806–6819.