![]() DNA hypermethylation can alter genetic stability and genomic structure, and is associated with transcriptional silencing of gene expression (commonly referred to as epigenetic silencing reviewed in Baylin and Jones, 2011 Esteller, 2008 Hassler and Egger, 2012). Among the various epigenetic alterations of cancer genomes, abnormal gains of DNA methylation in normally unmethylated gene promoter CpG islands have been the most extensively investigated. could represent promising targets for the development of new anti-cancer drugs.Įpigenetic dysregulation of gene expression plays a major role in the initiation and progression of cancer (reviewed in Baylin and Jones, 2011 Esteller, 2008 Hassler and Egger, 2012). ![]() Since they are a crucial part of the pathway linking a cancer-causing mutation to increased tumor growth, the proteins identified by Serra, Fang et al. showed that ZNF304, but not KRAS, was also involved in keeping these genes switched off until the stem cells started changing into specific types of cells. In these embryonic stem cells, Serra, Fang et al. Mutant KRAS caused an increase in the levels of these two proteins, which in turn caused the elevated ZNF304 levels and the excessive marking of the DNA in the tumor suppressor genes.įurthermore, some of these same tumor suppressor genes are switched off in the earliest cells in a human embryo-which have the potential to become any of 200 or so cell types in the human body. found that the levels of ZNF304 protein were elevated in colorectal cancer cells with the mutated KRAS, and showed that this was due to the combined activities of two other proteins that prevented ZNF304 from being broken down in the cell. ZNF304 is a protein that binds to stretches of DNA, including regions of DNA at the start of several tumor suppressor genes, and it recruits the enzymes that add the chemical marks that switch off these genes. In the absence of ZNF304, these tumor suppressor genes remained switched on in cancer cells with the KRAS mutation, so the growth of the tumor was slowed down. ![]() have identified a protein, called ZNF304, that is required by KRAS to switch off a large number of genes, including multiple tumor suppressors. These marks ‘switch off’ these genes, and although the identities of the enzymes that typically leave these marks on DNA are known, the link between these enzymes and the KRAS protein is unknown. Moreover, about 70% of colorectal cancers with a KRAS mutation also have an excess of small chemical marks on other genes, some of which are known to suppress the growth of tumors. Mutations that change the gene encoding a protein called KRAS are found in many different types of cancer. Like these other cancers, this disease is caused by mutations to genes that allow cells to multiply in an out of control manner. Finally, we show that ZNF304 also directs transcriptional silencing of INK4-ARF in human embryonic stem cells.Ĭolorectal cancer, which affects the large intestine, is a leading cause of cancer deaths worldwide, ranking fourth after cancers of the lung, stomach, and liver. KRAS promotes silencing through upregulation of ZNF304, which drives DNA binding. Promoter-bound ZNF304 recruits a corepressor complex that includes the DNA methyltransferase DNMT1, resulting in DNA hypermethylation and transcriptional silencing. In KRAS-positive human CRC cell lines and tumors, ZNF304 is bound at the promoters of INK4-ARF and other CIMP genes. In this study, we perform an RNA interference screen and identify ZNF304, a zinc-finger DNA-binding protein, as the pivotal factor required for INK4-ARF silencing and CIMP in CRCs containing activated KRAS. Among the CIMP genes are the tumor suppressors p14 ARF, p15 INK4B, and p16 INK4A, encoded by the INK4-ARF locus. The factors involved in, and the mechanistic basis of, CIMP is not understood. Approximately 70% of KRAS-positive colorectal cancers (CRCs) have a CpG island methylator phenotype (CIMP) characterized by aberrant DNA hypermethylation and transcriptional silencing of many genes.
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