Program in Gene Function and Expression; Program in Molecular Medicine; Department of Pathology
Biochemistry | Cancer Biology | Cell Biology | Molecular Biology
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. The factors involved in, and the mechanistic basis of, CIMP is not understood. Among the CIMP genes are the tumor suppressors p14(ARF), p15(INK4B), and p16(INK4A), encoded by the INK4-ARF locus. 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. In KRAS-positive human CRC cell lines and tumors, ZNF304 is bound at the promoters of INK4-ARF and other CIMP genes. Promoter-bound ZNF304 recruits a corepressor complex that includes the DNA methyltransferase DNMT1, resulting in DNA hypermethylation and transcriptional silencing. KRAS promotes silencing through upregulation of ZNF304, which drives DNA binding. Finally, we show that ZNF304 also directs transcriptional silencing of INK4-ARF in human embryonic stem cells. DOI: http://dx.doi.org/10.7554/eLife.02313.001.
CpG island methylator phenotype, DNMT1, INK4-ARF, KRAS, ZNF304, colorectal cancer
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Copyright 2014, Serra et al. This article is distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use and redistribution provided that the original author and source are credited.
DOI of Published Version
Serra RW, Fang M, Park SM, Hutchinson L, Green MR. A KRAS-directed transcriptional silencing pathway that mediates the CpG island methylator phenotype. Elife. 2014 Mar 12;3:e02313. doi: 10.7554/eLife.02313. Link to article on publisher's website
Serra, Ryan W.; Fang, Minggang; Park, Sung Mi; Hutchinson, Lloyd; and Green, Michael R., "A KRAS-directed transcriptional silencing pathway that mediates the CpG island methylator phenotype" (2014). Program in Molecular Medicine Publications and Presentations. 6.