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

Gong, Ping; Wang, Yuetong; Jing, Yongkui

doi:10.3390/ijms20071601

Cited by 48 publications

(40 citation statements)

References 137 publications

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“…Induction of apoptotic cell death represents one of the main mechanisms of anticancer effects promoted by HDAC inhibitors [ 57 , 58 , 59 , 60 , 61 ]. Regarding apoptosis signaling in cancer cells upon treatment with HDAC inhibitors, divergent effects have been demonstrated depending on the cellular context.…”

Section: Molecular Mechanisms Of Hdaci-promoted Anticancer Effectsmentioning

confidence: 99%

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Jenke

Reßing

Hansen

et al. 2021

Cancers

116

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The increasing knowledge of molecular drivers of tumorigenesis has fueled targeted cancer therapies based on specific inhibitors. Beyond “classic” oncogene inhibitors, epigenetic therapy is an emerging field. Epigenetic alterations can occur at any time during cancer progression, altering the structure of the chromatin, the accessibility for transcription factors and thus the transcription of genes. They rely on post-translational histone modifications, particularly the acetylation of histone lysine residues, and are determined by the inverse action of histone acetyltransferases (HATs) and histone deacetylases (HDACs). Importantly, HDACs are often aberrantly overexpressed, predominantly leading to the transcriptional repression of tumor suppressor genes. Thus, histone deacetylase inhibitors (HDACis) are powerful drugs, with some already approved for certain hematological cancers. Albeit HDACis show activity in solid tumors as well, further refinement and the development of novel drugs are needed. This review describes the capability of HDACis to influence various pathways and, based on this knowledge, gives a comprehensive overview of various preclinical and clinical studies on solid tumors. A particular focus is placed on strategies for achieving higher efficacy by combination therapies, including phosphoinositide 3-kinase (PI3K)-EGFR inhibitors and hormone- or immunotherapy. This also includes new bifunctional inhibitors as well as novel approaches for HDAC degradation via PROteolysis-TArgeting Chimeras (PROTACs).

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Section: Molecular Mechanisms Of Hdaci-promoted Anticancer Effectsmentioning

confidence: 99%

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Jenke

Reßing

Hansen

et al. 2021

Cancers

116

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“…More than 50 non-histone proteins, such as p53, Ku70, have been reported to be the substrates of HDACs. 46 So, we treated cells with trichostatin A (TSA), an inhibitor that is sensitive to Class I/II deacetylases, and then measured the impact of deacetylation inhibitor on DNA via Ku70-mediated IFN-k1 induction. The result indicated that treatment with TSA dosedependently increased IFN-k1 production (Figure 4E).…”

Section: Acetylation Regulates Ku70/dna-mediated Ifn-k1 Inductionmentioning

confidence: 99%

Cytoplasmic‐translocated Ku70 senses intracellular DNA and mediates interferon‐lambda1 induction

2021

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We have previously identified that human Ku70, a nuclear protein, serves as a cytosolic DNA sensor. Upon transfection with DNA or infection with DNA virus, Ku70 translocates from the nucleus into the cytoplasm and then predominately induces interferon lambda1 (IFN-k1) rather than IFN-alpha or IFN-beta, through a STING-dependent signalling pathway. However, a detailed mechanism for Ku70 cytoplasmic translocation and its correlation with IFN-k1 induction have not been fully elucidated. Here, we observed that cytoplasmic translocation of Ku70 only occurred in DNA-triggered IFN-k1-inducible cells. Additionally, infection by Herpes simplex virus type-1 (HSV-1), a DNA virus, induces cytoplasmic translocation of Ku70 and IFN-k1 induction in a strain-dependent manner: the translocation and IFN-k1 induction were detected upon infection by HSV-1 McKrae, but not MacIntyre, strain. A kinetic analysis indicated that cytoplasmic translocation of Ku70 was initiated right after DNA transfection and was peaked at 6 hr after DNA stimulation. Furthermore, treatment with leptomycin B, a nuclear export inhibitor, inhibited both Ku70 translocation and IFN-k1 induction, suggesting that Ku70 translocation is an essential and early event for its cytosolic DNA sensing. We further confirmed that enhancing the acetylation status of the cells promotes Ku70's cytoplasmic accumulation, and therefore increases DNA-mediated IFN-k1 induction. These findings provide insights into the molecular mechanism by which the versatile sensor detects pathogenic DNA in a localization-dependent manner.

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“…Notably, vorinostat has also been shown to induce necroptosis, a caspase-independent form of cell death [ 148 ]. Additionally, it was also suggested that HDACi cell death might be mediated by hyperacetylation of the NHEJ repair component Ku70 [ 149 , 150 , 151 ]. Ku70 acetylation and its interactions with Bax have been shown to be part of the apoptotic pathway, in a DNA repair-independent manner [ 152 ].…”

Section: Effects Of Hdac Inhibitors and Therapeutic Implications For Tumor Heterogeneitymentioning

confidence: 99%

HDAC Inhibitors: Dissecting Mechanisms of Action to Counter Tumor Heterogeneity

Karagiannis

Ράμπιας

2021

Cancers

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Intra-tumoral heterogeneity presents a major obstacle to cancer therapeutics, including conventional chemotherapy, immunotherapy, and targeted therapies. Stochastic events such as mutations, chromosomal aberrations, and epigenetic dysregulation, as well as micro-environmental selection pressures related to nutrient and oxygen availability, immune infiltration, and immunoediting processes can drive immense phenotypic variability in tumor cells. Here, we discuss how histone deacetylase inhibitors, a prominent class of epigenetic drugs, can be leveraged to counter tumor heterogeneity. We examine their effects on cellular processes that contribute to heterogeneity and provide insights on their mechanisms of action that could assist in the development of future therapeutic approaches.

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

Cited by 48 publications

References 137 publications

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Anticancer Therapy with HDAC Inhibitors: Mechanism-Based Combination Strategies and Future Perspectives

Cytoplasmic‐translocated Ku70 senses intracellular DNA and mediates interferon‐lambda1 induction

HDAC Inhibitors: Dissecting Mechanisms of Action to Counter Tumor Heterogeneity

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