Histone deacetylase inhibitors for cancer therapy: An evolutionarily ancient resistance response may explain their limited success

Halsall, John; Turner, Bryan M.

doi:10.1002/bies.201600070

Cited by 74 publications

(50 citation statements)

References 78 publications

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“…A form of methylation, H3K27me3, increased rapidly after 60 min. Therefore, it is thought that this response reverts protein hyperacetylation, counteracting the effects of HDAC inhibitors [89]. Similar results were obtained using VPA in the pluripotent, embryo-derived P19 mouse cell line, where protein and mRNA levels of two HATs (Cbp and p300), were downregulated [124].…”

Section: Histone Acetyltransferases (Hats) Downregulationsupporting

confidence: 60%

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Understanding Failure and Improving Treatment Using HDAC Inhibitors for Prostate Cancer

et al. 2020

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Novel treatment regimens are required for castration-resistant prostate cancers (CRPCs) that become unresponsive to standard treatments, such as docetaxel and enzalutamide. Histone deacetylase (HDAC) inhibitors showed promising results in hematological malignancies, but they failed in solid tumors such as prostate cancer, despite the overexpression of HDACs in CRPC. Four HDAC inhibitors, vorinostat, pracinostat, panobinostat and romidepsin, underwent phase II clinical trials for prostate cancers; however, phase III trials were not recommended due to a majority of patients exhibiting either toxicity or disease progression. In this review, the pharmacodynamic reasons for the failure of HDAC inhibitors were assessed and placed in the context of the advancements in the understanding of CRPCs, HDACs and resistance mechanisms. The review focuses on three themes: evolution of androgen receptor-negative prostate cancers, development of resistance mechanisms and differential effects of HDACs. In conclusion, advancements can be made in this field by characterizing HDACs in prostate tumors more extensively, as this will allow more specific drugs catering to the specific HDAC subtypes to be designed.

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Section: Histone Acetyltransferases (Hats) Downregulationsupporting

confidence: 60%

“…As a single agent, HDAC inhibitors have shown poor activity in CRPC and other solid tumors [2,89]. Previously, this has been attributed to their pharmacokinetic profile [90].…”

Section: Pharmacodynamic Rationale For Treatment Failure Using Hdac Imentioning

confidence: 99%

Understanding Failure and Improving Treatment Using HDAC Inhibitors for Prostate Cancer

et al. 2020

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“…In eukaryotes, DNA molecules are condensed into nucleosomes by forming complexes with histone proteins. Access to DNA and regulation of gene expression is mediated by histone acetylation and methylation (Turner, 2012;Halsall and Turner, 2016). The balance between histone acetylation by histone acetylases and deacetylation by histone deacetylases (HDAC) modulates transcription (Wang et al, 2009 Ca 2+…”

Section: Ampk and Histone Acetylationmentioning

confidence: 99%

The effects of obesity on skeletal muscle contractile function

Tallis

James

Seebacher

2018

Journal of Experimental Biology

156

146

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Obesity can cause a decline in contractile function of skeletal muscle, thereby reducing mobility and promoting obesity-associated health risks. We reviewed the literature to establish the current state-of-knowledge of how obesity affects skeletal muscle contraction and relaxation. At a cellular level, the dominant effects of obesity are disrupted calcium signalling and 5'-adenosine monophosphate-activated protein kinase (AMPK) activity. As a result, there is a shift from slow to fast muscle fibre types. Decreased AMPK activity promotes the class II histone deacetylase (HDAC)-mediated inhibition of the myocyte enhancer factor 2 (MEF2). MEF2 promotes slow fibre type expression, and its activity is stimulated by the calcium-dependent phosphatase calcineurin. Obesity-induced attenuation of calcium signalling via its effects on calcineurin, as well as on adiponectin and actinin affects excitation-contraction coupling and excitation-transcription coupling in the myocyte. These molecular changes affect muscle contractile function and phenotype, and thereby and muscle performance. , obesity can increase the absolute force and power produced by increasing the demand on weight-supporting muscle. However, when normalised to body mass, muscle performance of obese individuals is reduced. Isolated muscle preparations show that obesity often leads to a decrease in force produced per muscle cross-sectional area, and power produced per muscle mass. Obesity and ageing have similar physiological consequences. The synergistic effects of obesity and ageing on muscle function may exacerbate morbidity and mortality. Important future research directions include determining: the relationship between time course of weight gain and changes in muscle function; the relative effects of weight gain and high-fat diet feeding per se; the effects of obesity on muscle function during ageing; and if the effects of obesity on muscle function are reversible.

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“…Histone deacetylases (HDAC) are ubiquitously expressed epigenetic regulators by removing acetyl groups from the N-acetyl lysine amino acid on the tail of histone to silence gene transcription (16). HDACs have been found to deacetylate nonhistone proteins that are associated with various functions such as gene expression (17). Various HDAC isoforms differ in their subcellular location and targets, which account for their different biological functions.…”

Section: Introductionmentioning

confidence: 99%

HDAC3 Inhibition Upregulates PD-L1 Expression in B-Cell Lymphomas and Augments the Efficacy of Anti–PD-L1 Therapy

Deng

Zhang

et al. 2019

Molecular Cancer Therapeutics

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Programmed cell-death protein 1 (PD-1) and programmed death-ligand 1 (PD-L1) pathway blockade is a promising therapy for the treatment of advanced cancers, including B-cell lymphoma. The clinical response to PD-1/ PD-L1 immunotherapy correlates with PD-L1 levels on tumor cells and other cells in the tumor microenvironment. Hence, it is important to understand the molecular mechanisms that regulate PD-L1 expression. Here, we report that histone deacetylase 3 (HDAC3) is a crucial repressor of PD-L1 transcription in B-cell lymphoma. Pan-HDACs or selective HDAC3 inhibitors could rapidly increase histone acetylation and recruitment of bromodomain protein BRD4 at the promoter region of PD-L1 gene, leading to activation of its transcription. Mechanically, HDAC3 and its putative associated corepressor SMRT were recruited to the PD-L1 promoter by the transcriptional repressor BCL6. In addition, HDAC3 inhibition reduced DNA methyltransferase 1 protein levels to indirectly activate PD-L1 transcription. Finally, HDAC3 inhibition increased PD-L1 expression on dendritic cells in the tumor microenvironment. Combining selective HDAC3 inhibitor with anti-PD-L1 immunotherapy enhanced tumor regression in syngeneic murine lymphoma model. Our findings identify HDAC3 as an important epigenetic regulator of PD-L1 expression and implicate combination of HDAC3 inhibition with PD-1/PD-L1 blockade in the treatment of B-cell lymphomas.

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Histone deacetylase inhibitors for cancer therapy: An evolutionarily ancient resistance response may explain their limited success

Cited by 74 publications

References 78 publications

Understanding Failure and Improving Treatment Using HDAC Inhibitors for Prostate Cancer

Understanding Failure and Improving Treatment Using HDAC Inhibitors for Prostate Cancer

The effects of obesity on skeletal muscle contractile function

HDAC3 Inhibition Upregulates PD-L1 Expression in B-Cell Lymphomas and Augments the Efficacy of Anti–PD-L1 Therapy

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