Histone Deacetylase Inhibitors: Molecular and Biological Activity as a Premise to Clinical Application

Santini, Valeria; Gozzini, Antonella; Ferrari, Germano

doi:10.2174/138920007780655397

Cited by 124 publications

(85 citation statements)

References 77 publications

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“…HDAC inhibitors, such as SAHA, function by increasing histone (and non-histone) acetylation, which can lead to re-expression of epigenetically silenced genes (33,34). It has recently been demonstrated that treatment of breast cancer cell lines with histone deacetylase inhibitors can result in the re-expression of epigenetically silenced miRs (28 -30).…”

mentioning

confidence: 99%

miR-200a Regulates Nrf2 Activation by Targeting Keap1 mRNA in Breast Cancer Cells

Eades¹,

Yang²,

Yao

et al. 2011

Journal of Biological Chemistry

273

173

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NF-E2-related factor 2 (Nrf2) is an important transcription factor that activates the expression of cellular detoxifying enzymes. Nrf2 expression is largely regulated through the association of Nrf2 with Kelch-like ECH-associated protein 1 (Keap1), which results in cytoplasmic Nrf2 degradation. Conversely, little is known concerning the regulation of Keap1 expression. Until now, a regulatory role for microRNAs (miRs) in controlling Keap1 gene expression had not been characterized. By using miR array-based screening, we observed miR200a silencing in breast cancer cells and demonstrated that upon re-expression, miR-200a targets the Keap1 3-untranslated region (3-UTR), leading to Keap1 mRNA degradation. Loss of this regulatory mechanism may contribute to the dysregulation of Nrf2 activity in breast cancer. Previously, we have identified epigenetic repression of miR-200a in breast cancer cells. Here, we find that treatment with epigenetic therapy, the histone deacetylase inhibitor suberoylanilide hydroxamic acid, restored miR-200a expression and reduced Keap1 levels. This reduction in Keap1 levels corresponded with Nrf2 nuclear translocation and activation of Nrf2-dependent NAD(P)H-quinone oxidoreductase 1 (NQO1) gene transcription. Moreover, we found that Nrf2 activation inhibited the anchorage-independent growth of breast cancer cells. Finally, our in vitro observations were confirmed in a model of carcinogen-induced mammary hyperplasia in vivo. In conclusion, our study demonstrates that miR-200a regulates the Keap1/Nrf2 pathway in mammary epithelium, and we find that epigenetic therapy can restore miR200a regulation of Keap1 expression, therefore reactivating the Nrf2-dependent antioxidant pathway in breast cancer.

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mentioning

confidence: 99%

miR-200a Regulates Nrf2 Activation by Targeting Keap1 mRNA in Breast Cancer Cells

Eades¹,

Yang²,

Yao

et al. 2011

Journal of Biological Chemistry

273

173

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“…It is a potent histone deacetylase inhibitor isolated from Chromobacterium violaceum [50]. By inhibiting the acetylation of histone and nonhistone proteins, which broadly affects gene expression by enhancing cell-cycle arrest, apoptosis, growth inhibition, chromatin remodeling, tumor-suppressor gene transcription, and cellular differentiation [48,49,[51][52][53][54][55][56].…”

Section: Discussionmentioning

confidence: 99%

Subcutaneous Panniculitis-like T-cell Lymphoma: Review of Therapies

S¹,

Chaudhari²

2015

Intern Med

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Subcutaneous Panniculitis-like T-cell Lymphoma (SPTCL) is a rare subtype of cutaneous T-cell lymphoma derived from alpha/beta cytotoxic T-cells. It is known to follow an indolent course with a favorable prognosis. We review current therapies used to treat this rare entity in order to increase awareness about possible options. No standardized therapy for SPTL currently exists. Local radiotherapy for indolent local disease has been found successful. For indolent disease with a more generalized distribution, immunosuppressive agents as well as lowdose chemotherapy may be used. For aggressive presentations, combination chemotherapy, anthracycline-based regimens, fludarabine-based regimens, and rarely high-dose chemotherapy followed by hematopoietic stem cell transplant (SCT) with moderate success. By being aware of possible therapeutic options, a physician can recommend the most appropriate treatment for the individual.

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“…For example, an abundance of deacetylated histones is usually associated with chromatin structural change, which can lead to gene silencing and the genesis of cancer (27). Thus, a current anti-cancer strategy is to modulate gene expression by inducing chromatin remodeling through inhibiting histone deacetylases (HDACs).…”

Section: Discussionmentioning

confidence: 99%

Synergistic cytotoxicity of N-methyl-N'-nitro-N-nitrosoguanidine and absence of poly(ADP-ribose) glycohydrolase involves chromatin decondensation

Zhou

Feng²,

Koh

2011

Int J Oncol

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Abstract. DNA-alkylating agents in combination with poly (ADP-ribose) (PAR) synthesis inhibitors are a promising treatment for cancer. In search of other efficacious alternatives, we hypothesized that the absence of poly(ADP-ribose) glycohydrolase (PARG), which leads to the inhibition of PAR hydrolysis, would lead to increased DNA alkylation after treatment with low doses of N-methyl-N'-nitro-N-nitrosoguanidine (MNNG). At a sublethal dose, MNNG shows synergistic cytotoxicity in PARG-null embryonic trophoblast stem (TS) cells. The PAR modifications of histone H1 and histone H2B are much more pronounced in PARG null-TS cells exposed to MNNG, suggesting their relevance in the efficacy of this combination therapy. Because the PAR modification of these chromatin binding proteins leads to chromatin remodeling, a possible mechanism for the observed synergistic effects involves the subsequent decondensation of chromatin, which may cause the genomic DNA to be more accessible to MNNG alkylation. Further analysis demonstrated chromatin decondensation in PARG null-TS cells as visualized by electron microscopy. In addition, treatment with MNNG led to an increase in O 6 -methylguanine levels in PARG null-TS cells compared to wild-type, which demonstrates increased DNA alkylation in the absence of PARG. Taken together, we provide compelling evidence that the absence of PARG leads to chromatin decondensation, which in turn leads to increased amounts of DNA alkylation and cell death induced by low doses of MNNG. Therefore, combination therapy of PARG inhibition and a DNAalkylating agent is a potential treatment to induce the death of cancer cells.

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Histone Deacetylase Inhibitors: Molecular and Biological Activity as a Premise to Clinical Application

Cited by 124 publications

References 77 publications

miR-200a Regulates Nrf2 Activation by Targeting Keap1 mRNA in Breast Cancer Cells

miR-200a Regulates Nrf2 Activation by Targeting Keap1 mRNA in Breast Cancer Cells

Subcutaneous Panniculitis-like T-cell Lymphoma: Review of Therapies

Synergistic cytotoxicity of N-methyl-N'-nitro-N-nitrosoguanidine and absence of poly(ADP-ribose) glycohydrolase involves chromatin decondensation

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