Loss of the polycomb mark from bivalent promoters leads to activation of cancer-promoting genes in colorectal tumors.
In colon tumors, the transcription of many genes becomes deregulated by poorly defined epigenetic mechanisms that have been studied mainly in established cell lines. In this study, we used frozen human colon tissues to analyze patterns of histone modification and DNA cytosine methylation in cancer and matched normal mucosa specimens. DNA methylation is strongly targeted to bivalent H3K4me3- and H3K27me3-associated promoters, which lose both histone marks and acquire DNA methylation. However, we found that loss of the Polycomb mark H3K27me3 from bivalent promoters was accompanied often by activation of genes associated with cancer progression, including numerous stem cell regulators, oncogenes, and proliferation-associated genes. Indeed, we found many of these same genes were also activated in patients with ulcerative colitis where chronic inflammation predisposes them to colon cancer. Based on our findings, we propose that a loss of Polycomb repression at bivalent genes combined with an ensuing selection for tumor-driving events plays a major role in cancer progression.
Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA.
Maria A
MA
Hahn
Department of Information Sciences, Beckman Research Institute, City of Hope, Duarte, CA.
Arthur X
AX
Li
Department of Molecular Medicine, Beckman Research Institute, City of Hope, Duarte, CA.
Xiwei
X
Wu
Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA.
Richard
R
Yang
Center for Molecular Medicine, Univ. of Connecticut Health Center, Farmington, CT.
David A
DA
Drew
Center for Molecular Medicine, Univ. of Connecticut Health Center, Farmington, CT.
Daniel W
DW
Rosenberg
Department of Cancer Biology, Beckman Research Institute, City of Hope, Duarte, CA.
Gerd P
GP
Pfeifer
D049109:Cell Proliferation; D002471:Cell Transformation, Neoplastic / Q000235:genetics; D002843:Chromatin / Q000235:genetics; D047369:Chromatin Immunoprecipitation; D003093:Colitis, Ulcerative / Q000235:genetics; D015179:Colorectal Neoplasms / Q000235:genetics*; D019175:DNA Methylation; D018450:Disease Progression; D063185:Epigenetic Repression / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic; D006657:Histones / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D014411:Neoplastic Stem Cells / Q000166:cytology; D063146:Polycomb-Group Proteins / Q000235:genetics; D011401:Promoter Regions, Genetic / Q000235:genetics*; D014158:Transcription, Genetic
D002843:Chromatin; D006657:Histones; D063146:Polycomb-Group Proteins