HDACi - going through the mechanisms
Malgorzata Wanczyk1, Katarzyna Roszczenko1, Katarzyna Marcinkiewicz1,2, Kamil Bojarczuk1, Michal Kowara1, Magdalena Winiarska1
1
Department of Immunology, Centre of Biostructure Research, Medical University of Warsaw, Banacha 1A, F building, 02-097 Warsaw, Poland, 2Department of Pharmacology Weill Cornell Medical College and Graduate School of Medical Sciences of Cornell University, New York, USA
TABLE OF CONTENTS
- 1. Abstract
- 2. Introduction
- 3. Histone acetyltransferases
- 4.Histone deacetylases
- 5. Histone deacetylases and cancer
- 6. Histone deacetylases inhibitors
- 7. Acetylation of non-histone proteins
- 8. Mechanism of action of HDACi
- 8.1. Cytotoxicity
- 8.1.1. Apoptosis
- 8.1.1.1.HDACi activate both intrinsic and extrinsic apoptotic pathway
- 8.1.1.2. HDACi regulate the activity of tumor suppressors p53 and p73, important inducers of apoptosis.
- 8.1.1.3. HDACi target DNA-repairing enzymes involved in induction of apoptosis
- 8.1.1.4. HDACi modulate the activity of chaperone protein HSP90
- 8.1.1.5. HDACi influence redox state of the cancer cells and activate ROS-mediated apoptosis
- 8.1.2. Autophagy
- 8.2. Cell cycle arrest
- 8.3. Angiogenesis, metastasis and invasion
- 8.3.1. HDACi downregulate HIF-1alpha activity and target growth factors responsible for angiogenesis
- 8.3.2. HDACi downregulate matrix metalloproteinases MMP-2 and MMP-9
- 8.3.3. HDACi up-regulate the expression of angiostatic protein ADAMTS1
- 8.3.4. HDACi downregulate the expression of chemokine (C-X-C motif) receptor 4 (CXCR4)
- 8.3.5. HDACi downregulate the expression of endothelial nitric oxide synthase (eNOS) affecting endothelial cells vasorelaxation
- 8.4. Immunomodulatory effects of HDACi
9. HDACi in combination schemes
9.1. Combinations with chemotherapy
9.2. Combinations with irradiation
10. Resistance to HDACi
11. Conclusions
12. References
1. ABSTRACT
Histone deacetylases inhibitors (HDACi) have recently emerged as potent antitumor treatment modality. They are currently tested in many phase I, II and III clinical trials as single agents as wells as in combination schemes. They have demonstrated promising antitumor activity and favorable clinical outcome. Histone deacetylases (HDACs) are involved in the process of epigenetic regulation of gene expression. Epigenetic changes are believed to be crucial for the onset and progression of cancer and have recently gained remarkable attention. Since epigenetic regulation of gene expression is a reversible process, targeting histone deacetylases provides a good rationale for anticancer therapy. The acetylation status of histones regulates the organization of chromatin and the access of transcription factors. Moreover, functions of many non-histone proteins are controlled by acetylation. The broad and complicated influences of HDACi on various molecular processes may account for the observed pleiotropic effects. In this review we summarize recent advances in the understanding of biology of HDACs and mechanism of action of their inhibitors.
