The Biology of HDAC in Cancer The Nuclear and Epigenetic Components

Astrid Hagelkruys, Anna Sawicka, Magdalena Rennmayr, and Christian Seiser


1 The Role of HDAC Family Members in Development and Cancer 14

2 The Hallmarks of Cancer: Revisited 16

2.1 Proliferation and Cell Cycle Progression 16

2.2 Differentiation 20

2.3 Apoptosis 21

2.4 Metastasis 23

2.5 Angiogenesis 24

3 HDAC Involvement in Specific Tumor Development 25

3.1 Hematological Malignancies 25

3.2 Breast Cancer 26

3.3 Ovarian Cancer 27

3.4 Cancers of the Digestive System 27

3.5 Neuroblastoma 28

3.6 Prostate Cancer 28

3.7 Lung Cancer 29

4 Summary and Outlook 29

References 30

Abstract Traditionally, cancer has been regarded to originate from genetic alterations such as mutations, deletions, rearrangements as well as gene amplifications, leading to abnormal expression of tumor suppressor genes and oncogenes. An increasing body of evidence indicates that in addition to changes in DNA sequence, epigenetic alterations contribute to cancer initiation and progression. In contrast to genetic mutations, epigenetic changes are reversible and therefore an attractive target for cancer therapy. Many epi-drugs such as histone deacetylase (HDAC) inhibitors showed anticancer activity in cell culture and animal models of carcinogenesis.

Max F. Perutz Laboratories, Department of Medical Biochemistry, Medical University of Vienna, Vienna, Austria e-mail: [email protected]

T.-P. Yao and E. Seto (eds.), Histone Deacetylases: the Biology and Clinical Implication, 13 Handbook of Experimental Pharmacology 206, DOI 10.1007/978-3-642-21631-2_2, © Springer-Verlag Berlin Heidelberg 2011

Recently, the two HDAC inhibitors suberoylanilide hydroxamic acid (SAHA, Vorinostat) and Romidepsin (Depsipeptide, FK228) were FDA approved for the treatment of cutaneous T-cell lymphoma (CTCL). Although HDAC inhibitors are potent anticancer agents, these compounds act against several HDAC family members potentially resulting in numerous side effects. This stems from the fact that HDACs play crucial roles in a variety of biological processes including cell cycle progression, proliferation, differentiation, and development. Consistently, mice deficient in single HDACs mostly exhibit severe phenotypes. Therefore, it is necessary to specify the cancer-relevant HDACs in a given tumor type in order to design selective inhibitors that target only cancer cells without affecting normal cells. In this chapter, we summarize the current state of knowledge of individual nuclear HDAC family members in development and tumorigenesis, their contribution to the hallmarks of cancer, and the involvement of HDAC family members in different types of human malignancies.

Keywords Epigenetic therapy • Hallmarks of cancer • Malignancies • Tumorigenesis

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