[Frontiers in Bioscience 6, d610-629, April 1, 2001] 610 HISTONE ACETYLATION AND THE CELL-CYCLE IN CANCER 1 Chenguang Wang * , 1 Maufu Fu * , 1 Sridhar Mani, 1 Scott Wadler, 2 Adrian M. Senderowicz, 1 Richard G. Pestell 1 The Albert Einstein Comprehensive Cancer Center, Department of Developmental and Molecular Biology, Albert Einstein College of Medicine, Chanin 302, 1300 Morris Park Ave., Bronx, NY 10461. 2 Molecular Therapeutics Unit, Oral and Pharyngeal Cancer Branch, National Institute of Dental and Craniofacial Research, National Institutes of Health, Bldg. 30, Room 211, 30 Convent Drive, Bethesda, MD 20892-4340 TABLE OF CONTENTS 1. Abstract 2. Introduction 3. Chromatin modifying enzymes and mitogenic signaling. 4. Histone acetyltransferases and cancer. 5. Histone modification during the cell cycle, DNA damage and apoptosis 6. Histone deacetylases as cancer therapeutic targets. 7. Cyclin-dependent kinases and the regulation of histone acetylase activity. 8. Endogenous cyclin-dependent kinase inhibitors and histone acetylase activity. 9. Therapeutics targeting the cell cycle and histone deacetylation 9.1. Histone deacetylase (HDAC) inhibitors 9.1.1. Hybrid polar compounds 9.1.2. Benzamide derivatives 9.1.3.Trichostatins and cyclic tetrapeptide antibiotic 9.2. Cdk modulators as Novel Cancer Therapy 9.2.1.Flavopiridol. 9.2.2.Staurosporine analogues and UCN-01. 9.2.3.The Paullones 9.2.4.Indirect Modulators of CDK function. 10. Conclusion 11. Acknowledgement 12. References 1. ABSTRACT A number of distinct surveillance systems are found in mammalian cells that have the capacity to interrupt normal cell-cycle progression. These are referred to as cell cycle check points. Surveillance systems activated by DNA damage act at three stages, one at the G 1 /S phase boundary, one that monitors progression through S phase and one at the G 2 /M boundary. The initiation of DNA synthesis and irrevocable progression through G 1 phase represents an additional checkpoint when the cell commits to DNA synthesis. Transition through the cell cycle is regulated by a family of protein kinase holoenzymes, the cyclin-d ependent k inases (Cdks), and their heterodimeric cyclin partner. Orderly progression through the cell-cycle checkpoints involves coordinated activation of the Cdks that, in the presence of an associated Cdk-a ctivating k inase (CAK), phosphorylate target substrates including members of the "pocket protein" family. One of these, the product of the retinoblastoma susceptibility gene (the pRB protein), is phosphorylated sequentially by both cyclin D/Cdk4 complexes and cyclin E/Cdk2 kinases. Recent studies have identified important cross talk between the cell-cycle regulatory apparatus and proteins regulating histone acetylation. pRB binds both E2F proteins and histone deacetylase (HDAC) complexes. HDAC plays an important role in pRB tumor suppression function and transcriptional repression. Histones are required for accurate assembly of chromatin and the induction of histone gene expression is tightly coordinated. Recent studies have identified an important alternate substrate of cyclin E/Cdk2, NPAT (nuclear protein mapped to the ATM locus) which plays a critical role in promoting cell-cycle progression in the absence of pRB, and contributes to cell-cycle regulated histone gene expression. The acetylation of histones by a number of histone acetyl transferases (HATs) also plays an important role in coordinating gene expression and cell-cycle progression. Components of the cell-cycle regulatory apparatus are both regulated by HATs and bind directly to HATs. Finally transcription factors have been identified as substrate for HATs. Mutations of these transcription factors at their sites of acetylation has been associated with constitutive activity