tailieunhanh - 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 to promoter/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. | 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 to promoter 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 the activity of transcription factors in modulating the histone code and the methylation status of the genetic regulatory elements of genes. The pattern of gene transcription is aberrant in all human cancers and in many cases epigenetic events are responsible. Unlike genetic events that alter DNA primary structure . deletions epigenetic changes are potentially reversible and appear amenable to therapeutic intervention. In many human cancers including pancreatic cancer and multiple myeloma the p16Ink4a promoter is inactivated by methylation thus permitting the unchecked activity of CDK4 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 epigenetically silenced. Other targeted genes include the p15Ink4b CDK inhibitor glutathione-S-transferase which detoxifies reactive oxygen species and the E-cadherin molecule important for junction formation between epithelial cells . Epigenetic silencing can occur in premalignant lesions and can affect genes involved in DNA repair thus predisposing to further genetic damage. .