Chapter 080. Cancer Cell Biology and Angiogenesis (Part 9)

Acetylation of the amino terminus of the core histones H3 and H4 induces an open chromatin conformation that promotes transcription initiation. Histone acetylases are components of coactivator complexes recruited topromoter/enhancer regions by sequence-specific transcription factors during the activation of genes (Fig. 80-4). Histone deacetylases (HDACs; at least 17 are encoded in the human genome) are recruited to genes by transcriptional repressors and prevent the initiation of gene transcription. Methylated cytosine residues in promoter regions become associated with methyl-cytosine–binding proteins that recruit protein complexes with HDAC activity. The balance between permissive and inhibitory chromatin structure is therefore largely determined by...
Nội dung trích xuất từ tài liệu:
Chapter 080. Cancer Cell Biology and Angiogenesis (Part 9) Chapter 080. Cancer Cell Biology and Angiogenesis (Part 9) Acetylation of the amino terminus of the core histones H3 and H4 inducesan open chromatin conformation that promotes transcription initiation. Histoneacetylases are components of coactivator complexes recruited topromoter/enhancer regions by sequence-specific transcription factors during theactivation of genes (Fig. 80-4). Histone deacetylases (HDACs; at least 17 areencoded in the human genome) are recruited to genes by transcriptional repressorsand prevent the initiation of gene transcription. Methylated cytosine residues inpromoter regions become associated with methyl-cytosine–binding proteins thatrecruit protein complexes with HDAC activity. The balance between permissiveand inhibitory chromatin structure is therefore largely determined by the activityof transcription factors in modulating the histone code and the methylation statusof the genetic regulatory elements of genes. The pattern of gene transcription is aberrant in all human cancers, and inmany cases, epigenetic events are responsible. Unlike genetic events that alterDNA primary structure (e.g., deletions), epigenetic changes are potentiallyreversible and appear amenable to therapeutic intervention. In many humancancers, including pancreatic cancer and multiple myeloma, the p16 Ink4a promoteris inactivated by methylation, thus permitting the unchecked activity ofCDK4/cyclin D and rendering pRB nonfunctional. In sporadic forms of renal,breast, and colon cancer, the von Hippel–Lindau (VHL), breast cancer 1 (BRCA1),and serine/threonine kinase 11 (STK11) genes, respectively, are epigeneticallysilenced. Other targeted genes include the p15Ink4b CDK inhibitor, glutathione-S-transferase (which detoxifies reactive oxygen species), and the E-cadherinmolecule (important for junction formation between epithelial cells). Epigeneticsilencing can occur in premalignant lesions and can affect genes involved in DNArepair, thus predisposing to further genetic damage. Examples include MLH1 (mutL homologue) in hereditary nonpolyposis colon cancer (HNPCC, also calledLynch syndrome), which is critical for repair of mismatched bases that occurduring DNA synthesis, and 06-methylguanine-DNA methyltransferase, whichremoves alkylated guanine adducts from DNA and is often silenced in colon, lung,and lymphoid tumors. Many human leukemias have chromosomal translocations that code fornovel fusion proteins with enzymatic activities that alter chromatin structure. ThePML-RAR fusion protein, generated by the t(15;17) observed in most cases ofacute promyelocytic leukemia (APL), binds to promoters containing retinoic acidresponse elements and recruits HDAC to these promoters, effectively inhibitinggene expression. This arrests differentiation at the promyelocyte stage andpromotes tumor cell proliferation and survival. Treatment with pharmacologicdoses of all-trans retinoic acid (ATRA), the ligand for RARα, results in the releaseof HDAC activity and the recruitment of coactivators, which overcomes thedifferentiation block. This induced differentiation of APL cells has greatlyimproved treatment of these patients and has provided a treatment paradigm forthe reversal of epigenetic changes in cancer. However, for other leukemia-associated fusion proteins, such as AML-ETO and the MLL fusion proteins seenin AML and ALL, no ligand is known. Therefore, efforts are ongoing to determinethe structural basis for interactions between translocation fusion proteins andchromatin remodeling proteins, and to use this information to rationally designsmall molecules that will disrupt specific protein-protein associations. Drugs thatblock the enzymatic activity of HDAC are being developed. A number of differentchemical classes of HDAC inhibitors have demonstrated antitumor activity inclinical studies against cutaneous T cell lymphoma (e.g., vorinostat) and somesolid tumors. HDAC inhibitors may target cancer cells via a number ofmechanisms including upregulation of death receptors (DR4/5, FAS, and theirligands) and p21Cip1/Waf1, as well as inhibition of cell cycle checkpoints. Major therapeutic efforts are also under way to reverse thehypermethylation of CpG islands that characterizes many solid tumors. Drugs thatinduce DNA demethylation, such as 5-aza-2-deoxycytidine, can lead toreexpression of silenced genes in cancer cells with restoration of function.However, 5-aza-2-deoxycytidine has limited aqueous solubility and ismyelosuppressive. Other inhibitors of DNA methyltransferases are indevelopment. In ongoing clinical trials, inhibitors of DNA methylation are beingcombined with HDAC inhibitors. The hope is that by reversing coexistingepigenetic changes, the deregulated patterns of gene transcription in cancer cellswill be at least partially reversed. Aberrant signal transduction pathways activate a number of transcriptionfactors that promote tumor cell proliferation and survival. These include signaltransducer and activator of transcription (STAT)-3 and STAT5, NFκB, β-catenin(a component of the APC tumor-suppressor pathway), the heterodimer of c-Junand Fos known as AP1, and c-Myc. The ability to target these transcription factorstherapeutically does not currently exist. However, structural and molecularapproaches may make it possible to identify small molecules that would inhibitprotein-protein interactions needed for transcription factor dimerization orinteraction with coactivator proteins. A small-molecule inhibitor has beendeveloped that blocks the association of Myc with its partner Max, therebyinhibit ...