Targeting Histone Deacetylase 8 as a Therapeutic Approach to Cancer and Neurodegenerative Diseases

Chakrabarti, Alokta; Melesina, Jelena; Kolbinger, Fiona R.; Oehme, Ina; Senger, Johanna; Witt, Olaf; Sippl, Wolfgang; Jung, Manfred

doi:10.4155/fmc-2016-0117

Cited by 87 publications

(56 citation statements)

References 121 publications

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“…Moreover, HDAC8 has been implicated in inactivation of the tumor suppressor p53 in acute myeloid leukemia stem cells (Qi et al, 2015). These observations have led to the proposal that HDAC8 is a potential target for cancer treatment (Chakrabarti et al, 2016). Indeed, a number of HDAC8-specific inhibitors are in early development for the treatment of cancer.…”

Section: Discussionmentioning

confidence: 99%

Cooperativity of HOXA5 and STAT3 Is Critical for HDAC8 Inhibition-Mediated Transcriptional Activation of PD-L1 in Human Melanoma Cells

Wang

Liu

Sherwin

et al. 2018

Journal of Investigative Dermatology

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Although the expression of programmed death-ligand 1 (PD-L1) is an important mechanism by which cancer cells evade the immune system, PD-L1 expression in cancer cells is commonly associated with patients' responses to treatment with anti-programmed death 1/PD-L1 antibodies. However, how PD-L1 expression is regulated in melanoma cells remains to be fully elucidated. Here we report that the class I histone deacetylase (HDAC) HDAC8 controls transcriptional activation of PD-L1 by a transcription complex consisting of transcription factors homeobox A5 and signal transducer and activator of transcription 3. Inhibition of HDAC8 upregulated PD-L1 in melanoma cells. This was due to an increase in the activity of a fragment of the PD-L1 gene promoter that is enriched with binding sites for both homeobox A5 and signal transducer and activator of transcription 3. Indeed, knockdown of homeobox A5 or signal transducer and activator of transcription 3 abolished upregulation of PD-L1 by HDAC8 inhibition. Moreover, homeobox A5 and signal transducer and activator of transcription 3 were physically associated and appeared interdependent in activating PD-L1 transcription. Functional studies showed that HDAC8-mediated regulation of PD-L1 expression participated in modulating anti-melanoma T-cell responses. Collectively, these results identify HDAC8 as an important epigenetic regulator of PD-L1 expression, with implications for better understanding of the interaction between melanoma cells and the immune system.

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Section: Discussionmentioning

confidence: 99%

Cooperativity of HOXA5 and STAT3 Is Critical for HDAC8 Inhibition-Mediated Transcriptional Activation of PD-L1 in Human Melanoma Cells

Wang

Liu

Sherwin

et al. 2018

Journal of Investigative Dermatology

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“…The 4-methoxybenzyl ts into the subpocket of HDAC8 which may be a reason for the selectivity toward HDAC8 enzyme. 90 Zhang et al reported a series of tetrahydroisoquinolinebased hydroxamic acid HDACis. 91 The tertiary butyloxycarbonyl (Boc) group was located on the secondary amine atom and 4-methyloxy-phenyl group seemed benecial to HDAC8 inhibitory activity.…”

Section: Class I Selective Hdacismentioning

confidence: 99%

Next-generation of selective histone deacetylase inhibitors

Yang

Zhao

et al. 2019

RSC Adv.

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“…In fact, several HDAC inhibitors have been applied for treatment of T-cell lymphoma, such as SAHA (suberoylanilide hydroxamic acid, Vorinostat) (Negmeldin and Pflum, 2017) and Belinostat (Poole, 2014), and Panobinostat (Garnock-Jones, 2015). Unfortunately, these FDA approved drugs are relatively non-selective and inhibit most of the zincdependent HDAC subtypes (Yang, 2011;Qiao et al, 2013), which could cause several mild or severe toxic effects associated with the treatment, such as dehydration, thrombocytopenia, anorexia, and cardiac arrhythmia (Chakrabarti et al, 2016;Buonvicino et al, 2018;Cosenza and Pozzi, 2018;Laino et al, 2019). In addition, due to the physicochemical properties of hydroxamic acid group as the ZBG, some drawbacks have been exposed, including poor stability, easy metabolism, weak binding ability to class IIa isozymes, and poor selectivity, making the design and discovery of HDAC inhibitors with novel zinc binding group (ZBG) more necessary (Di Micco et al, 2008;Botta et al, 2011;Burli et al, 2013;Zhao et al, 2018;Banerjee et al, 2019).…”

Section: Introductionmentioning

confidence: 99%

Synthesis and Biological Evaluation of HDAC Inhibitors With a Novel Zinc Binding Group

Wang

Liu

et al. 2020

Front. Chem.

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Vorinostat (SAHA) with great therapeutic potential has been approved by the FDA for the treatment of cutaneous T-cell lymphoma as the first HDACs inhibitor, but the drawbacks associated with hydroxamic acid group (poor stability, easy metabolism, weak binding ability to class IIa isozymes, and poor selectivity) have been exposed during the continuous clinical application. Based on the pharmacophore of HDAC inhibitors, two series of compounds with novel zinc binding group (ZBG) were designed and synthesized, and the antitumor bioactivities were evaluated in four human cancer cell lines (A549, Hela, HepG2, and MCF-7). Among the synthesized compounds, compounds a6, a9, a10, b8, and b9 exhibited promising inhibitory activities against the selected tumor cell lines, especially compounds a9 and b8 on Hela's cytostatic activity (a9: IC 50 = 11.15 ± 3.24 µM; b8: IC 50 = 13.68 ± 1.31 µM). The enzyme inhibition assay against Hela extracts and HDAC1&6 subtypes showed that compound a9 had a certain broad-spectrum inhibitory activity, while compound b8 had selective inhibitory activity against HDAC6, which was consistent with Western blot results. In addition, the inhibitory mechanism of compounds a9 and b8 in HDAC1&6 were both compared through computational approaches, and the binding interactions between the compounds and the enzymes target were analyzed from the perspective of energy profile and conformation. In summary, the compounds with novel ZBG exhibited certain antitumor activities, providing valuable hints for the discovery of novel HDAC inhibitors.

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Targeting Histone Deacetylase 8 as a Therapeutic Approach to Cancer and Neurodegenerative Diseases

Cited by 87 publications

References 121 publications

Cooperativity of HOXA5 and STAT3 Is Critical for HDAC8 Inhibition-Mediated Transcriptional Activation of PD-L1 in Human Melanoma Cells

Cooperativity of HOXA5 and STAT3 Is Critical for HDAC8 Inhibition-Mediated Transcriptional Activation of PD-L1 in Human Melanoma Cells

Next-generation of selective histone deacetylase inhibitors

Synthesis and Biological Evaluation of HDAC Inhibitors With a Novel Zinc Binding Group

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