Recent progress in DNA methyltransferase inhibitors as anticancer agents

Zhang, Zhixiong; Wang, Guan; Li, Yuyan; Lei, Dongsheng; Xiang, Jun; Ouyang, Liang; Wang, Yanyan; Yang, Jinliang

doi:10.3389/fphar.2022.1072651

Cited by 24 publications

(14 citation statements)

References 126 publications

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“…When combined with hydralazine, which can also affect DNA methylation, the combined action on chromatin structure and gene regulation may potentiate the cytotoxic effects of doxorubicin ( Fig 2B ) [ 40 ]. The combined effects of doxorubicin and hydralazine on cell cycle progression may lead to enhanced cytotoxicity by preventing cancer cells from repairing DNA damage and proliferating [ 41 ] ( Fig 2C ).…”

Section: Resultsmentioning

confidence: 99%

Synergistic combination of doxorubicin with hydralazine, and disulfiram against MCF-7 breast cancer cell line

Lafi,

Alshaer,

Gharaibeh

et al. 2023

PLoS ONE

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Disulfiram and hydralazine have recently been reported to have anti-cancer action, and repositioned to be used as adjuvant in cancer therapy. Chemotherapy combined with other medications, such as those that affect the immune system or epigenetic cell profile, can overcome resistance with fewer adverse effects compared to chemotherapy alone. In the present study, a combination of doxorubicin (DOX) with hydrazine (Hyd) and disulfiram (Dis), as a triple treatment, was evaluated against wild-type and DOX-resistant MCF-7 breast cancer cell line. Both wild-type MCF-7 cell line (MCF-7_WT) and DOX-resistant MCF-7 cell line (MCF-7_DoxR) were treated with different combination ratios of DOX, Dis, and Hyd followed by measuring the cell viability using the MTT assay. Synergism was determined using a combination index, isobologram analysis, and dose-reducing index. The anti-proliferation activity and mechanism of the triple combination were investigated by apoptosis analysis. The results showed a reduction in the IC50 values of DOX in MCF-7_WT cells (from 0.24 μM to 0.012 μM) and MCF-7_DoxR cells (from 1.13 μM to 0.44 μM) when treated with Dis (0.03μM), and Hyd (20μM) combination. Moreover, The triple combination DOX/Hyd/Dis induced significant apoptosis in both MCF-7_WT and MCF-7_DoxR cells compared to DOX alone. The triple combination of DOX, Dis, and Hyd showed a synergistic drugs combination to decrease the DOX dose needed to kill both MCF-7_WT and MCF-7_DoxR cancer cells and enhanced chemosensitivity to DOX.

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Section: Resultsmentioning

confidence: 99%

Synergistic combination of doxorubicin with hydralazine, and disulfiram against MCF-7 breast cancer cell line

Lafi,

Alshaer,

Gharaibeh

et al. 2023

PLoS ONE

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“…We observed that the promoter region of TEAD4 could be heavily methylated. Therefore, the use of DNA methyltransferase inhibitors (such as decitabine or azacitidine) may be a potential treatment option for certain tumor types [38]. In some tumors, TEAD4-∆N may be overexpressed, making its silencing potentially beneficial.…”

Section: Discussionmentioning

confidence: 99%

“…This is because current DNA methyltransferase inhibitors and TET inhibitors may cause mutations that lead to malformations during embryonic development. A new generation of DNA methylation inhibitors is on the horizon, which may increase their potential use for implantation-related issues [38] in the future.…”

Section: Discussionmentioning

confidence: 99%

Integrative Epigenetic and Molecular Analysis Reveals a Novel Promoter for a New Isoform of the Transcription Factor TEAD4

Rashidiani,

Mamo,

Farkas

et al. 2024

IJMS

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TEAD4 is a transcription factor that plays a crucial role in the Hippo pathway by regulating the expression of genes related to proliferation and apoptosis. It is also involved in the maintenance and differentiation of the trophectoderm during pre- and post-implantation embryonic development. An alternative promoter for the TEAD4 gene was identified through epigenetic profile analysis, and a new transcript from the intronic region of TEAD4 was discovered using the 5’RACE method. The transcript of the novel promoter encodes a TEAD4 isoform (TEAD4-ΔN) that lacks the DNA-binding domain but retains the C-terminal protein–protein interaction domain. Gene expression studies, including end-point PCR and Western blotting, showed that full-length TEAD4 was present in all investigated tissues. However, TEAD4-ΔN was only detectable in certain cell types. The TEAD4-ΔN promoter is conserved throughout evolution and demonstrates transcriptional activity in transient-expression experiments. Our study reveals that TEAD4 interacts with the alternative promoter and increases the expression of the truncated isoform. DNA methylation plays a crucial function in the restricted expression of the TEAD4-ΔN isoform in specific tissues, including the umbilical cord and the placenta. The data presented indicate that the DNA-methylation status of the TEAD4-ΔN promoter plays a critical role in regulating organ size, cancer development, and placenta differentiation.

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“…Epigenetic silencing of tumor suppressor genes (TSG) is a common hallmark of cancer. This phenomenon has been classically associated to DNA hypermethylation of TSG promoter proximal regions 50 , and has driven the research and implementation of inhibitors of DNA methylation in a wider range of cancer 51 . While an EZH2 inhibitor has been approved for clinical usage 52 , its application is still limited to EZH2 mutated cancers.…”

Section: Discussionmentioning

confidence: 99%

Super-silencer perturbation by EZH2 and REST inhibition leads to large loss of chromatin interactions and reduction in cancer growth

Zhang,

Chen,

Tang

et al. 2023

Preprint

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Human silencers have been shown to exist and regulate developmental gene expression. However, the functional importance of human silencers needs to be elucidated, such as whether they can form "super-silencers" and whether they are linked to cancer progression. Here, through interrogating two putative silencer components of FGF18 gene, we found that two nearby silencers can cooperate via compensatory chromatin interactions to form a "super-silencer". Furthermore, double knockout of two silencers exhibited synergistic upregulation of FGF18 expression and changes of cell identity. To perturb the "super-silencers", we applied combinational treatment of an EZH2 inhibitor GSK343, and a REST inhibitor, X5050 ("GR"). We found that GR led to severe loss of TADs and loops, while the use of one inhibitor by itself only showed mild changes. Such changes in TADs and loops were associated with reduced CTCF and TOP2A mRNA levels. Moreover, GSK343 and X5050 synergistically upregulated super-silencer-controlled genes related to cell cycle, apoptosis and DNA damage, leading to anticancer effects both in vitro and in vivo. Overall, our data demonstrated the first example of a "super-silencer" and showed that combinational usage of GSK343 and X5050 to disrupt "super-silencers" could potentially lead to cancer ablation.

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Recent progress in DNA methyltransferase inhibitors as anticancer agents

Cited by 24 publications

References 126 publications

Synergistic combination of doxorubicin with hydralazine, and disulfiram against MCF-7 breast cancer cell line

Synergistic combination of doxorubicin with hydralazine, and disulfiram against MCF-7 breast cancer cell line

Integrative Epigenetic and Molecular Analysis Reveals a Novel Promoter for a New Isoform of the Transcription Factor TEAD4

Super-silencer perturbation by EZH2 and REST inhibition leads to large loss of chromatin interactions and reduction in cancer growth

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