Targeting Histone Deacetylases in Malignant Melanoma: A Future Therapeutic Agent or Just Great Expectations?

Garmpis, Nikolaos; Damaskos, Christos; Garmpi, Anna; Dimitroulis, Dimitrios; Spartalis, Eleftherios; Margonis, Georgios Antonios; Schizas, Dimitrios; Deskou, Irini; Doula, Chrysoula; Magkouti, Eleni; Andreatos, Nikolaos; Antoniou, Efstathios; Nonni, Afroditi; Kontzoglou, Konstantinos; Mantas, Dimitrios

doi:10.21873/anticanres.11961

Cited by 20 publications

(17 citation statements)

References 27 publications

(59 reference statements)

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“…Sirtinol has many off-target effects, as there are iron chelation and biological effects below the SIRT protein inhibition levels. However, as a pharmacological inhibition of SIRT1, Sirtinol effectively inhibited the expressions of SIRT1 and SIRT2 and was used to inhibit SIRT1 signaling in several studies [ 22 , 46 , 47 ]. In our study, we also showed intervention with SIRT1 significantly decreased the SIRT1 expression following TBI.…”

Section: Discussionmentioning

confidence: 99%

Omega-3 polyunsaturated fatty acid attenuates the inflammatory response by modulating microglia polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway following experimental traumatic brain injury

Chen

et al. 2018

J Neuroinflammation

167

103

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BackgroundMicroglial polarization and the subsequent neuroinflammatory response are contributing factors for traumatic brain injury (TBI)-induced secondary injury. High mobile group box 1 (HMGB1) mediates the activation of the NF-κB pathway, and it is considered to be pivotal in the late neuroinflammatory response. Activation of the HMGB1/NF-κB pathway is closely related to HMGB1 acetylation, which is regulated by the sirtuin (SIRT) family of proteins. Omega-3 polyunsaturated fatty acids (ω-3 PUFA) are known to have antioxidative and anti-inflammatory effects. We previously demonstrated that ω-3 PUFA inhibited TBI-induced microglial activation and the subsequent neuroinflammatory response by regulating the HMGB1/NF-κB signaling pathway. However, no studies have elucidated if ω-3 PUFA affects the HMGB1/NF-κB pathway in a HMGB1 deacetylation of dependent SIRT1 manner, thus regulating microglial polarization and the subsequent neuroinflammatory response.MethodsThe Feeney DM TBI model was adopted to induce brain injury in rats. Modified neurological severity scores, rotarod test, brain water content, and Nissl staining were employed to determine the neuroprotective effects of ω-3 PUFA supplementation. Assessment of microglia polarization and pro-inflammatory markers, such as tumor necrosis factor (TNF)-α, interleukin (IL)-1β, IL-6, and HMGB1, were used to evaluate the neuroinflammatory responses and the anti-inflammatory effects of ω-3 PUFA supplementation. Immunofluorescent staining and western blot analysis were used to detect HMGB1 nuclear translocation, secretion, and HMGB1/NF-κB signaling pathway activation to evaluate the effects of ω-3 PUFA supplementation. The impact of SIRT1 deacetylase activity on HMGB1 acetylation and the interaction between HMGB1 and SIRT1 were assessed to evaluate anti-inflammation effects of ω-3 PUFAs, and also, whether these effects were dependent on a SIRT1-HMGB1/NF-κB axis to gain further insight into the mechanisms underlying the development of the neuroinflammatory response after TBI.ResultsThe results of our study showed that ω-3 PUFA supplementation promoted a shift from the M1 microglial phenotype to the M2 microglial phenotype and inhibited microglial activation, thus reducing TBI-induced inflammatory factors. In addition, ω-3 PUFA-mediated downregulation of HMGB1 acetylation and its extracellular secretion was found to be likely due to increased SIRT1 activity. We also found that treatment with ω-3 PUFA inhibited HMGB1 acetylation and induced direct interactions between SIRT1 and HMGB1 by elevating SIRT1 activity following TBI. These events lead to inhibition of HMGB1 nucleocytoplasmic translocation/extracellular secretion and alleviated HMGB1-mediated activation of the NF-κB pathway following TBI-induced microglial activation, thus inhibiting the subsequent inflammatory response.ConclusionsThe results of this study suggest that ω-3 PUFA supplementation attenuates the inflammatory response by modulating microglial polarization through SIRT1-mediated deacetylation of the HMGB1/...

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Section: Discussionmentioning

confidence: 99%

Omega-3 polyunsaturated fatty acid attenuates the inflammatory response by modulating microglia polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway following experimental traumatic brain injury

Chen

et al. 2018

J Neuroinflammation

167

103

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“…In addition, since TSA treatment reduced the expression of TLE3 (data not shown) it is also possible that the suppressive effect of TSA on the proliferation of melanoma is due to direct HDAC repression of TLE3 expression. HDAC inhibitors also induce apoptosis in several kinds of malignant tumor cells [2]. Our preliminary data showed that over-expression of Tle3 reduced the number of apoptotic B16 cells induced by TSA treatment (data not shown), indicating that the reduction of apoptosis by Tle3 may be involved in the regulation of B16 tumor size by Tle3.…”

Section: Discussionmentioning

confidence: 87%

“…A characteristic feature of melanoma is rapid cell proliferation [2]. Tle3 has been shown to stimulate cell proliferation in skeletal muscle satellite cells [12].…”

Section: Resultsmentioning

confidence: 99%

“…The worldwide incidence of melanoma has been steadily increasing with mortality rates rising faster than any other form of cancer [1]. Melanoma cells are derived from the neural crest and characterized by rapid proliferation and numerous distal metastasis [2]. Recently, major advancements have been achieved for metastatic melanomas via the blockade of immune-checkpoints using a programmed death 1 (PD-1) checkpoint inhibitor and a cytotoxic T-lymphocyte-associated antigen 4 (CTLA-4) checkpoint inhibitor [3].…”

Section: Introductionmentioning

confidence: 99%

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Transducin-like enhancer of split 3 regulates proliferation of melanoma cells via histone deacetylase activity

et al. 2019

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Melanoma, one of the most aggressive neoplasms, is characterized by rapid cell proliferation. Transducin-like Enhancer of Split (TLE) is an important regulator of cell proliferation via Histone deacetylase (HDAC) recruitment. Given that HDAC activity is associated with melanoma progression, we examined the relationship between TLE3, a TLE family member, and melanoma. TLE3 expression was increased during the progression of human patient melanoma (p < 0.05). Overexpression of Tle3 in B16 murine melanoma cells led to an increase in cell proliferation (p < 0.01) as well as the number of cyclinD1-positive cells. in vivo injection of mice with B16 cells overexpressing Tle3 resulted in larger tumor formation than in mice injected with control cells (p < 0.05). In contrast, siRNA-mediated knockdown of Tle3 in B16 cells or TLE3 in HMV-II human melanoma cells decreased proliferation (p < 0.01). Treatment of B16 cells with trichostatin A (2.5 μM), a class I and II HDAC inhibitor, prevented the effect s of Tle3 on proliferation. In conclusion, these data indicate that Tle3 is required, at least in part, for proliferation in the B16 mouse melanoma model.

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“…HDACis are compounds that were shown to induce growth arrest of transformed cells, cell death, angiogenesis inhibition, and terminal differentiation [ 106 , 107 ]. Human HDACs, grouped into four classes based on the similarity of DNA sequences and function include 18 different substances [ 108 ]. It has been proven that HDACis induce dormancy of micrometastatic disease through differentiation of UM cells and shift UM cells from Class 2 to the Class 1 signature [ 35 ].…”

Section: Potential Of Epigenetic Therapies In Ummentioning

confidence: 99%

Targeting Epigenetic Modifications in Uveal Melanoma

Baradaran

Kozovská

Furdová

et al. 2020

IJMS

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Uveal melanoma (UM), the most common intraocular malignancy in adults, is a rare subset of melanoma. Despite effective primary therapy, around 50% of patients will develop the metastatic disease. Several clinical trials have been evaluated for patients with advanced UM, though outcomes remain dismal due to the lack of efficient therapies. Epigenetic dysregulation consisting of aberrant DNA methylation, histone modifications, and small non-coding RNA expression, silencing tumor suppressor genes, or activating oncogenes, have been shown to play a significant role in UM initiation and progression. Given that there is no evidence any approach improves results so far, adopting combination therapies, incorporating a new generation of epigenetic drugs targeting these alterations, may pave the way for novel promising therapeutic options. Furthermore, the fusion of effector enzymes with nuclease-deficient Cas9 (dCas9) in clustered regularly interspaced short palindromic repeats (CRISPR) associated protein 9 (Cas9) system equips a potent tool for locus-specific erasure or establishment of DNA methylation as well as histone modifications and, therefore, transcriptional regulation of specific genes. Both, CRISPR-dCas9 potential for driver epigenetic alterations discovery, and possibilities for their targeting in UM are highlighted in this review.

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Targeting Histone Deacetylases in Malignant Melanoma: A Future Therapeutic Agent or Just Great Expectations?

Abstract: Abstract. Background

Cited by 20 publications

References 27 publications

Omega-3 polyunsaturated fatty acid attenuates the inflammatory response by modulating microglia polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway following experimental traumatic brain injury

Omega-3 polyunsaturated fatty acid attenuates the inflammatory response by modulating microglia polarization through SIRT1-mediated deacetylation of the HMGB1/NF-κB pathway following experimental traumatic brain injury

Transducin-like enhancer of split 3 regulates proliferation of melanoma cells via histone deacetylase activity

Targeting Epigenetic Modifications in Uveal Melanoma

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