Histone acetylation and the cell-cycle in cancer

A number of distinct surveillance systems are found in mammalian cells that have the capacity to interrupt normal cell-cycle progression. These are re ferred 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 mon itors progression through S phase and one at the G(2)/M boundary. The initi ation of DNA synthesis and irrevocable progression through G(1) phase repre sents an additional checkpoint when the cell commits to DNA synthesis. Tran sition through the cell cycle is regulated by a family of protein kinase ho loenzymes, the cyclin-dependent kinases (Cdks), and their heterodimeric cyc lin partner. Orderly progression through the cell-cycle checkpoints involve s coordinated activation of the Cdks that, in the presence of an associated Cdk-activating kinase (CAK), phosphorylate target substrates including mem bers of the "pocket protein" family. One of these, the product of the retin oblastoma susceptibility gene (the pRB protein), is phosphorylated sequenti ally 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 repres sion. Histones are required for accurate assembly of chromatin and the indu ction of histone gene expression is tightly coordinated. Recent studies hav e identified an important alternate substrate of cyclin E/Cdk2, NPAT (nucle ar protein mapped to the ATM locus) which plays a critical role in promotin g cell-cycle progression in the absence of pRB, and contributes to cell-cyc le regulated histone gene expression. The acetylation of histones by a numb er of histone acetyl transferases (HATs) also plays an important role in co ordinating gene expression and cell-cycle progression. Components of the ce ll-cycle regulatory apparatus are both regulated by HATs and bind directly to HATs. Finally transcription factors have been identified as substrate fo r HATs. Mutations of these transcription factors at their sites of acetylat ion has been associated with constitutive activity and enhanced cellular pr oliferation, suggesting an important role for acetylation in transcriptiona l repression as well as activation. Together these studies provide a workin g model in which the cell-cycle regulatory kinases phosphorylate and inacti vate HDACs, coordinate histone gene expression and bind to histone acetylas es themselves. The recent evidence for cross-talk between the cyclin-depend ent kinases and histone gene expression on the one hand and cyclin-dependen t regulation of histone acetylases on the other, suggests chemotherapeutics targeting histone acetylation may have complex and possibly complementary effects with agents targeting Cdks.