Epigenetic Regulators of DNA Cytosine Modification: Promising Targets for Cancer Therapy

Jung, Inkyung; An, Jeong Ho; Ko, Myunggon

doi:10.3390/biomedicines11030654

Cited by 5 publications

(2 citation statements)

References 172 publications

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“…Several pharmacological activators exhibit direct or indirect TET agonism, demonstrating clinical efficacy in cancer treatment. Vitamin C accelerates the recycling of Fe(II), an essential cofactor of TET enzymes, thereby augmenting TET activity [30,31]. Consistent with frequent TET inactivation in cancers, physiological vitamin C levels are markedly reduced in many cancer patients, compared with healthy individuals [32][33][34].…”

Section: Introductionmentioning

confidence: 99%

Development of Novel Epigenetic Anti-Cancer Therapy Targeting TET Proteins

Kim,

Jung,

Lee

et al. 2023

IJMS

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Epigenetic dysregulation, particularly alterations in DNA methylation and hydroxymethylation, plays a pivotal role in cancer initiation and progression. Ten-eleven translocation (TET) proteins catalyze the successive oxidation of 5-methylcytosine (5mC) to 5-hydroxymethylcytosine (5hmC) and further oxidized methylcytosines in DNA, thereby serving as central modulators of DNA methylation–demethylation dynamics. TET loss of function is causally related to neoplastic transformation across various cell types while its genetic or pharmacological activation exhibits anti-cancer effects, making TET proteins promising targets for epigenetic cancer therapy. Here, we developed a robust cell-based screening system to identify novel TET activators and evaluated their potential as anti-cancer agents. Using a carefully curated library of 4533 compounds provided by the National Cancer Institute, Bethesda, MD, USA, we identified mitoxantrone as a potent TET agonist. Through rigorous validation employing various assays, including immunohistochemistry and dot blot studies, we demonstrated that mitoxantrone significantly elevated 5hmC levels. Notably, this elevation manifested only in wild-type (WT) but not TET-deficient mouse embryonic fibroblasts, primary bone marrow-derived macrophages, and leukemia cell lines. Furthermore, mitoxantrone-induced cell death in leukemia cell lines occurred in a TET-dependent manner, indicating the critical role of TET proteins in mediating its anti-cancer effects. Our findings highlight mitoxantrone’s potential to induce tumor cell death via a novel mechanism involving the restoration of TET activity, paving the way for targeted epigenetic therapies in cancer treatment.

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Section: Introductionmentioning

confidence: 99%

Development of Novel Epigenetic Anti-Cancer Therapy Targeting TET Proteins

Kim,

Jung,

Lee

et al. 2023

IJMS

Self Cite

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“…As a result, DNA methylation abnormalities exhibit significant impacts on all stages of oncogenesis from its onset to progression to metastasis, which may eventually lead to tumor chemotherapy resistance. Thus, DNA methylation/demethylation pathway as a promising target for therapeutic intervention in cancer ( 6 ). Studies have shown that hypermethylation in promoters of Reversion-inducing cysteine-rich protein with kazal motifs (RECK), RAS association domain family protein1A gene (RASSF1), Suprabasin promotes the metastasis and progression of SACC, which is associated with poor prognosis of patients ( 7 - 9 ).…”

Section: Introductionmentioning

confidence: 99%

Silencing of AJAP1 expression by promoter methylation activates the Wnt/β-catenin signaling pathway to promote tumor proliferation and metastasis in salivary adenoid cystic carcinoma

Jiang¹,

Liu²,

Pan³

et al. 2023

Gland Surg

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Background Salivary adenoid cystic carcinoma (SACC) is a unique malignant tumor of the salivary gland with poor prognosis, which is not effective with chemotherapy and targeted drugs. Therefore, it is important to explore the molecular mechanism underlying SACC invasion and metastasis to develop novel therapeutic strategies and targets in clinical research. Methods Real-time quantitative polymerase chain reaction (RT-qPCR) and western blot (WB) were performed to detect the expression of Adherens Junctions Associated Protein 1 ( AJAP1 ). Methylation-specific PCR was used to evaluate the methylation of the AJAP1 promoter. AJAP1 was overexpressed or knocked down by lentivirus-mediated transfection. Kaplan-Meier analysis was conducted to create a survival curve and the log-rank test was used to analyze the overall survival (OS). The prognostic correlation was assessed using univariate and multivariate Cox regression analyses. Co-immunoprecipitation (Co-IP) was utilized to pull down the possible binding protein of AJAP1 and laser scanning confocal microscopy was applied to detect the subcellular localization of AJAP1 , E-cadherin, and β-catenin. Cell viability, colony formation, wound healing, and Transwell invasion assays were performed to evaluate the function of AJAP1 in vitro . A subcutaneous xenograft assay in nude mice was performed to verify the function of AJAP1 in vivo . Results AJAP1 was downregulated in SACC tumors and was closely related to SACC lymph node/distant metastasis, which was an independent risk factor for SACC prognosis. Methylation-specific PCR confirmed that high methylation of the AJAP1 promoter was the main cause of its silencing. Overexpression or knockdown of AJAP1 in SACC cells could significantly inhibit or promote the proliferation, invasion, and metastasis of SACC cells, respectively, in both the in vitro and in vivo experiments. Mechanically, we found that AJAP1 binds to E-cadherin and β-catenin to form a complex in cytomembrane, reducing the nuclear translocation of β-catenin and blocking the Wingless/Integrated/β-catenin (Wnt/β-catenin) signaling pathway to play a suppressive role in cancer. Conclusions In conclusion, these results suggest that the downregulation of AJAP1 protein expression may play a certain role in progression and metastasis of SACC. Our study indicates that AJAP1 may be a potential prognostic molecular marker and therapeutic target for SACC.

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