Global levels of H3K27me3 track with differentiation in vivo and are deregulated by MYC in prostate cancer.
Cancer cells and stem cells share a number of biological characteristics including abundant amounts of decondensed chromatin. However, the molecular correlates and the factors involved in altering chromatin structure in cancer cells are not well known. Here, we report that less differentiated stem-like cells in the basal compartment of human and mouse prostate contain lower levels of the polycomb heterochromatin marker H3K27me3 than more differentiated luminal cells. This link to differentiated normal cells is also found in a number of other human and rodent tissues characterized by hierarchical differentiation. In addition to MYC's traditional role as a gene-specific transcription factor, recent studies indicate that MYC also affects global chromatin structure where it is required to maintain "open" or active chromatin. We now demonstrate that in both MYC-driven prostate cancers in mice and human prostate cancers, global levels of H3K27me3 are reduced in prostatic intraepithelial neoplasia and invasive adenocarcinoma lesions. Moreover, decreased levels of H3K27me3 correlate with increased markers of disease aggressiveness (eg, Gleason score and pathological stage). In vitro, experimentally forced reductions in MYC levels result in increased global levels of H3K27me3. These findings suggest that increased levels of decondensed chromatin in both normal progenitor cells and cancer cells are associated with global loss of H3K27me3, which is linked to MYC overexpression.
Department of Pathology, The Johns Hopkins University School of Medicine, Baltimore, Maryland, USA.
Laxmi G
LG
Pellakuru
Tsuyoshi
T
Iwata
Bora
B
Gurel
Denise
D
Schultz
Jessica
J
Hicks
Carlise
C
Bethel
Srinivasan
S
Yegnasubramanian
Angelo M
AM
De Marzo
D000818:Animals; D002451:Cell Compartmentation; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D000071221:Enhancer of Zeste Homolog 2 Protein; D006657:Histones / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D007249:Inflammation / Q000378:metabolism / Q000473:pathology; D008239:Lysine / Q000378:metabolism*; D008297:Male; D008745:Methylation; D051379:Mice; D009928:Organ Specificity; D063151:Polycomb Repressive Complex 2 / Q000378:metabolism; D011467:Prostate / Q000378:metabolism / Q000473:pathology / Q000601:surgery; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000378:metabolism* / Q000473:pathology* / Q000601:surgery; D011499:Protein Processing, Post-Translational; D016271:Proto-Oncogene Proteins c-myc / Q000378:metabolism*; D034741:RNA, Small Interfering / Q000378:metabolism; D013234:Stem Cells / Q000378:metabolism; D046888:Tissue Array Analysis
D006657:Histones; D016271:Proto-Oncogene Proteins c-myc; D034741:RNA, Small Interfering; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D063151:Polycomb Repressive Complex 2; D008239:Lysine