Vorinostat exhibits anticancer effects in triple-negative breast cancer cells by preventing nitric oxide-driven histone deacetylation

Palczewski, Marianne B.; Kuschman, Hannah Petraitis; Bovee, Rhea C.; Hickok, Jason R.; Thomas, Douglas D.

doi:10.1515/hsz-2020-0323

Cited by 8 publications

(5 citation statements)

References 36 publications

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“…In cells exposed to exogenous NO or in cells endogenously synthesizing NO, the rates of cell migration and invasion were increased compared to untreated control cells (Fig. 4B-D), consistent with what we and others have shown previously 6, 45 . Another phenotype associated with tumor aggressiveness is resistance to chemotherapy.…”

Section: Resultssupporting

confidence: 92%

Nitric oxide inhibits ten-eleven translocation DNA demethylases to regulate 5mC and 5hmC across the genome

Thomas,

Palczewski,

Kuschman

et al. 2024

Preprint

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DNA methylation at cytosine bases of eukaryotic DNA (5-methylcytosine, 5mC) is a heritable epigenetic mark that can regulate gene expression in health and disease. Enzymes that metabolize 5mC have been well-characterized, yet the discovery of endogenously produced signaling molecules that regulate DNA methyl-modifying machinery have not been described. Herein, we report that the free radical signaling molecule nitric oxide (NO) can directly inhibit the Fe(II)/2-OG-dependent DNA demethylases ten-eleven translocation (TET) and human AlkB homolog 2 (ALKBH2). Physiologic NO concentrations reversibly inhibited TET and ALKBH2 demethylase activity by binding to the mononuclear non-heme iron atom which formed a dinitrosyliron complex (DNIC) preventing cosubstrates (2-OG and O2) from binding. In cancer cells treated with exogenous NO, or cells endogenously synthesizing NO, there was a global increase in 5mC and 5-hydroxymethylcytosine (5hmC) in DNA, the substrates for TET, that could not be attributed to increased DNA methyltransferase activity. 5mC was also elevated in NO-producing cell-line-derived mouse xenograft and patient-derived xenograft tumors. Genome-wide DNA methylome analysis of cells chronically treated with NO (10 days) demonstrated enrichment of 5mC and 5hmC at gene-regulatory loci which correlated to changes in the expression of NO-regulated tumor-associated genes. Regulation of DNA methylation is distinctly different from canonical NO signaling and represents a novel epigenetic role for NO.

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Section: Resultssupporting

confidence: 92%

Nitric oxide inhibits ten-eleven translocation DNA demethylases to regulate 5mC and 5hmC across the genome

Thomas,

Palczewski,

Kuschman

et al. 2024

Preprint

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“…42 The HDAC inhibitor, Vorinostat (SAHA, developed by Merck) has not only been approved as a treatment agent for T-cell lymphoma but is also undergoing phase 2 and 3 clinical trials for breast cancer and non-small cell lung cancer. 43 Since inhibitors of DNMTs, EZH2 or HDACs are all non-specific with regulatory effects on numerous genes, combinations of these drugs may effectively enhance efficacy and reduce side effects. 44 In the present study, we showed that compared with the control and sin-…”

Section: Discussionmentioning

confidence: 99%

Downregulation of MEG3 and upregulation of EZH2 cooperatively promote neuroblastoma progression

Gao

Chen

et al. 2022

J Cellular Molecular Medi

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Neuroblastoma (NB), an embryonic tumour originating from sympathetic crest cells, is the most common extracranial solid tumour type in children with poor overall prognosis. Accumulating evidence has demonstrated the involvement of long non-coding RNA (lncRNA) in numerous biological processes and their associations with embryonic development and multiple diseases. Ectopic lncRNA expression is linked to malignant tumours. Previous studies by our team indicate that MEG3 attenuates NB autophagy through inhibition of FOXO1 and epithelial-mesenchymal transition via the mTOR pathway in vitro. Moreover, MEG3 and EZH2 negatively regulate each other. In present study, we first collected 60 NB tissues and 20 adjacent tissues for Quantitative real-time polymerase chain reaction (Q-PCR) experiments and performed clinical correlation analysis of the results. At the same time, nude mice were used for subcutaneous tumour formation to detect the effect of MEG3 in vivo. Two NB cell lines, SK-N-AS and SK-N-BE(2)C, were overexpressed MEG3 and rescued with EZH2 and then were subjected to proliferation, migration, invasion, apoptosis and autophagy experiments. RNA-binding protein immunoprecipitation (RIP) and Co-Immunoprecipitation (Co-IP) experiments were performed to explore the molecular mechanism of MEG3 and EZH2 interaction. Q-PCR revealed that MEG3 expression was negatively correlated with INSS stage and risk grade of NB. Moreover, MEG3 overexpression was associated with inhibition of NB growth in vivo. MEG3 exerted an anti-cancer effect via stimulatory effects on EZH2 ubiquitination leading to its degradation. Conversely,

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“…The HDAC catalytic activity inhibition by SAHA is based on its binding to the zinc ion located in the enzyme catalytic domain [ 58 , 94 ]. It has been demonstrated that SAHA shows the anti-proliferative acitivity of human cancer cell lines [ 95 , 96 , 97 ], including BC [ 98 , 99 , 100 ].…”

Section: Saha and Breast Cancermentioning

confidence: 99%

Vorinostat (SAHA) and Breast Cancer: An Overview

Wawruszak

Borkiewicz

Okon

et al. 2021

Cancers

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Vorinostat (SAHA), an inhibitor of class I and II of histone deacetylases, is the first histone deacetylase inhibitor (HDI) approved for the treatment of cutaneous T-cell lymphoma in 2006. HDIs are promising anticancer agents that inhibit the proliferation of many types of cancer cells including breast carcinoma (BC). BC is a heterogeneous disease with variable biological behavior, morphological features, and response to therapy. Although significant progress in the treatment of BC has been made, high toxicity to normal cells, serious side effects, and the occurrence of multi-drug resistance limit the effective therapy of BC patients. Therefore, new active agents which improve the effectiveness of currently used regimens are highly needed. This manuscript analyzes preclinical and clinical trials data of SAHA, applied individually or in combination with other anticancer agents, considering different histological subtypes of BC.

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Vorinostat exhibits anticancer effects in triple-negative breast cancer cells by preventing nitric oxide-driven histone deacetylation

Cited by 8 publications

References 36 publications

Nitric oxide inhibits ten-eleven translocation DNA demethylases to regulate 5mC and 5hmC across the genome

Nitric oxide inhibits ten-eleven translocation DNA demethylases to regulate 5mC and 5hmC across the genome

Downregulation of MEG3 and upregulation of EZH2 cooperatively promote neuroblastoma progression

Vorinostat (SAHA) and Breast Cancer: An Overview

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