Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells

Wawruszak, Anna; Kałafut, Joanna; Okon, Estera; Czapiński, Jakub; Hałasa, Marta; Przybyszewska, Alicja; Miziak, Paulina; Okła, Karolina; Rivero-Müller, Adolfo; Stepulak, Andrzej

doi:10.3390/cancers11020148

Cited by 81 publications

(74 citation statements)

References 129 publications

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“…HDACs are being considered as therapeutic targets for cancer treatment. An array of natural and synthetic compounds inhibiting HDAC activity, referred to as HDAC inhibitor (HDACi), have been developed [10,11,12]. Although increased histone acetylation by HDACi treatment has been observed, this phenomenon could not be linked to therapeutic outcome.…”

Section: Introductionmentioning

confidence: 99%

Apoptosis Induction byHistone Deacetylase Inhibitors in Cancer Cells: Role of Ku70

Gong

Wang

Jing

2019

IJMS

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Histone deacetylases (HDACs) are a group of enzymes that regulate gene transcription by controlling deacetylation of histones and non-histone proteins. Overexpression of HDACs is found in some types of tumors and predicts poor prognosis. Five HDAC inhibitors are approved for the treatment of cutaneous T-cell lymphoma, peripheral T-cell lymphoma, and multiple myeloma. Treatment with HDAC inhibitors regulates gene expression with increased acetylated histones with unconfirmed connection with therapy. Apoptosis is a key mechanism by which HDAC inhibitors selectively kill cancer cells, probably due to acetylation of non-histone proteins. Ku70 is a protein that repairs DNA breaks and stabilizes anti-apoptotic protein c-FLIP and proapoptotic protein Bax, which is regulated by acetylation. HDAC inhibitors induce Ku70 acetylation with repressed c-FLIP and activated Bax in cancer cells. Current studies indicate that Ku70 is a potential target of HDAC inhibitors and plays an important role during the induction of apoptosis.

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Section: Introductionmentioning

confidence: 99%

Apoptosis Induction byHistone Deacetylase Inhibitors in Cancer Cells: Role of Ku70

Gong

Wang

Jing

2019

IJMS

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“…The human HDAC family consists of 18 proteins divided into 4 classes. These proteins modulate, among others, the transcription of genes encoding proteins involved in carcinogenesis [57].…”

Section: Inhibitors Of Histone Deacetylase (Hdac)mentioning

confidence: 99%

Thiadiazole derivatives as anticancer agents

Szeliga

2020

Pharmacol. Rep

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In spite of substantial progress made toward understanding cancer pathogenesis, this disease remains one of the leading causes of mortality. Thus, there is an urgent need to develop novel, more effective anticancer therapeutics. Thiadiazole ring is a versatile scaffold widely studied in medicinal chemistry. Mesoionic character of this ring allows thiadiazole-containing compounds to cross cellular membrane and interact strongly with biological targets. Consequently, these compounds exert a broad spectrum of biological activities. This review presents the current state of knowledge on thiadiazole derivatives that demonstrate in vitro and/or in vivo efficacy across the cancer models with an emphasis on targets of action. The influence of the substituent on the compounds’ activity is depicted. Furthermore, the results from clinical trials assessing thiadiazole-containing drugs in cancer patients are summarized.

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“…HDACs have been linked to oncogenesis through multiple mechanisms, to date it is known that there is more than one mechanism through which HDACs play their role in carcinogenesis. Many studies demonstrated that both through over-expression [27,28,29,30,31,32] or aberrant interaction with transcriptional regulators [33,34,35,36] HDACs mediate the transcriptional repression of oncosuppressor genes [27,28,29,30,31,33,34,35,36]. Furthermore, different HDACs have shown to have cell context specific roles and to play different pro or anti-cancer activity depending on tumor type.…”

Section: Hdac Proteinsmentioning

confidence: 99%

“…Furthermore, different HDACs have shown to have cell context specific roles and to play different pro or anti-cancer activity depending on tumor type. The differential role of HDACs and the implication of HDAC targeting depending on the context have been extensively reviewed by Wawruszak et al [36].…”

Section: Hdac Proteinsmentioning

confidence: 99%

Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy

Manzotti

Ciarrocchi

Sancisi

2019

Cancers

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Histone DeACetylases (HDACs) are enzymes that remove acetyl groups from histones and other proteins, regulating the expression of target genes. Pharmacological inhibition of these enzymes re-shapes chromatin acetylation status, confusing boundaries between transcriptionally active and quiescent chromatin. This results in reinducing expression of silent genes while repressing highly transcribed genes. Bromodomain and Extraterminal domain (BET) proteins are readers of acetylated chromatin status and accumulate on transcriptionally active regulatory elements where they serve as scaffold for the building of transcription-promoting complexes. The expression of many well-known oncogenes relies on BET proteins function, indicating BET inhibition as a strategy to counteract their activity. BETi and HDACi share many common targets and affect similar cellular processes to the point that combined inhibition of both these classes of proteins is regarded as a strategy to improve the effectiveness of these drugs in cancer. In this work, we aim to discuss the molecular basis of the interplay between HDAC and BET proteins, pointing at chromatin acetylation as a crucial node of their functional interaction. We will also describe the state of the art of their dual inhibition in cancer therapy. Finally, starting from their mechanism of action we will provide a speculative perspective on how these drugs may be employed in combination with standard therapies to improve effectiveness and/or overcome resistance.

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Histone Deacetylase Inhibitors and Phenotypical Transformation of Cancer Cells

Cited by 81 publications

References 129 publications

Apoptosis Induction byHistone Deacetylase Inhibitors in Cancer Cells: Role of Ku70

Apoptosis Induction byHistone Deacetylase Inhibitors in Cancer Cells: Role of Ku70

Thiadiazole derivatives as anticancer agents

Inhibition of BET Proteins and Histone Deacetylase (HDACs): Crossing Roads in Cancer Therapy

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