Role of HDACs in normal and malignant hematopoiesis

Wang, Pan; Wang, Zi; Liu, Jing

doi:10.1186/s12943-019-1127-7

Cited by 137 publications

(141 citation statements)

References 170 publications

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“…Following the successful results with SAHA, many other HDACis have been approved for the clinical treatment in various hematological tumors such as romidepsin or belinostat. Unfortunately, hematological tumor cells have developed drug resistance to HDACis, which promoted the regeneration and maintenance of the malignant phenotype (Wang et al, 2020). The molecular basis for drug resistance by HDACis is still unclear, although drug efflux, chromatin alteration, upregulation of oxidative stress response mechanism, defects or upregulation in apoptotic pathways have been implicated (Wang et al, 2020).…”

Section: Hdacis Treatment To Enhance the Anticancer Efficacymentioning

confidence: 99%

Synergistic Enhancement of Cancer Therapy Using HDAC Inhibitors: Opportunity for Clinical Trials

et al. 2020

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Chemotherapy is one of the most established and effective treatments for almost all types of cancer. However, the elevated toxicity due to the non-tumor-associated effects, development of secondary malignancies, infertility, radiation-induced fibrosis and resistance to treatment limit the effectiveness and safety of treatment. In addition, these multiple factors significantly impact quality of life. Over the last decades, our increased understanding of cancer epigenetics has led to new therapeutic approaches and the promise of improved patient outcomes. Epigenetic alterations are commonly found in cancer, especially the increased expression and activity of histone deacetylases (HDACs). Dysregulation of HDACs are critical to the development and progression of the majority of tumors. Hence, HDACs inhibitors (HDACis) were developed and now represent a very promising treatment strategy. The use of HDACis as monotherapy has shown very positive pre-clinical results, but clinical trials have had only limited success. However, combinatorial regimens with other cancer drugs have shown synergistic effects both in pre-clinical and clinical studies. At the same time, these combinations have enhanced the efficacy, reduced the toxicity and tumor resistance to therapy. In this review, we will examine examples of HDACis used in combination with other cancer drugs and highlight the synergistic effects observed in recent preclinical and clinical studies.

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Section: Hdacis Treatment To Enhance the Anticancer Efficacymentioning

confidence: 99%

Synergistic Enhancement of Cancer Therapy Using HDAC Inhibitors: Opportunity for Clinical Trials

et al. 2020

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“…By that, HDACs have a significant influence on the function and stability of their target proteins and regulate multiple cellular pathways and biological processes including proliferation, differentiation and survival ( 6 , 7 ). As a consequence, HDACs are considered a promising therapeutic target for the treatment of a variety of diseases and several inhibitors are currently under investigation particularly in different types of cancer ( 8 – 10 ), but also cardiovascular and neurodegenerative disorders, inflammation and fibrosis ( 11 – 15 ). Vorinostat and romidepsin, for example, are pan-HDAC inhibitors being approved for the treatment of T-cell lymphoma.…”

Section: Introductionmentioning

confidence: 99%

Liver-Specific Knockdown of Class IIa HDACs Has Limited Efficacy on Glucose Metabolism but Entails Severe Organ Side Effects in Mice

et al. 2020

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Histone deacetylases (HDACs) are important regulators of epigenetic gene modification that are involved in the transcriptional control of metabolism. In particular class IIa HDACs have been shown to affect hepatic gluconeogenesis and previous approaches revealed that their inhibition reduces blood glucose in type 2 diabetic mice. In the present study, we aimed to evaluate the potential of class IIa HDAC inhibition as a therapeutic opportunity for the treatment +of metabolic diseases. For that, siRNAs selectively targeting HDAC4, 5 and 7 were selected and used to achieve a combinatorial knockdown of these three class IIa HDAC isoforms. Subsequently, the hepatocellular effects as well as the impact on glucose and lipid metabolism were analyzed in vitro and in vivo . The triple knockdown resulted in a statistically significant decrease of gluconeogenic gene expression in murine and human hepatocyte cell models. A similar HDAC-induced downregulation of hepatic gluconeogenesis genes could be achieved in mice using a liver-specific lipid nanoparticle siRNA formulation. However, the efficacy on whole body glucose metabolism assessed by pyruvate-tolerance tests were only limited and did not outweigh the safety findings observed by histopathological analysis in spleen and kidney. Mechanistically, Affymetrix gene expression studies provide evidence that class IIa HDACs directly target other key factors beyond the described forkhead box (FOXP) transcription regulators, such as hepatocyte nuclear factor 4 alpha (HNF4a). Downstream of these factors several additional pathways were regulated not merely including glucose and lipid metabolism and transport. In conclusion, the liver-directed combinatorial knockdown of HDAC4, 5 and 7 by therapeutic siRNAs affected multiple pathways in vitro , leading in vivo to the downregulation of genes involved in gluconeogenesis. However, the effects on gene expression level were not paralleled by a significant reduction of gluconeogenesis in mice. Combined knockdown of HDAC isoforms was associated with severe adverse effects in vivo , challenging this approach as a treatment option for chronic metabolic disorders like type 2 diabetes.

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“…After the publication of this work [1], the authors note that there are no figure legends in the published paper. So we supplement the figure legends in this correction draft.…”

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confidence: 99%