Global levels of H3K27me3 track with differentiation in Vivo and are deregulated by MYC in prostate cancer

Laxmi G. Pellakuru, Tsuyoshi Iwata, Bora Gurel, Denise Schultz, Jessica Hicks, Carlise Bethel, S Yegnasubramanian, Angelo Michael Demarzo

Research output: Contribution to journalArticle

Abstract

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.

Original languageEnglish (US)
Pages (from-to)560-569
Number of pages10
JournalAmerican Journal of Pathology
Volume181
Issue number2
DOIs
StatePublished - Aug 2012

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Chromatin
Prostatic Neoplasms
Stem Cells
Prostatic Intraepithelial Neoplasia
Neoplasms
Heterochromatin
Neoplasm Grading
Prostate
Rodentia
Adenocarcinoma
Transcription Factors
Genes

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

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Global levels of H3K27me3 track with differentiation in Vivo and are deregulated by MYC in prostate cancer. / Pellakuru, Laxmi G.; Iwata, Tsuyoshi; Gurel, Bora; Schultz, Denise; Hicks, Jessica; Bethel, Carlise; Yegnasubramanian, S; Demarzo, Angelo Michael.

In: American Journal of Pathology, Vol. 181, No. 2, 08.2012, p. 560-569.

Research output: Contribution to journalArticle

Pellakuru, Laxmi G. ; Iwata, Tsuyoshi ; Gurel, Bora ; Schultz, Denise ; Hicks, Jessica ; Bethel, Carlise ; Yegnasubramanian, S ; Demarzo, Angelo Michael. / Global levels of H3K27me3 track with differentiation in Vivo and are deregulated by MYC in prostate cancer. In: American Journal of Pathology. 2012 ; Vol. 181, No. 2. pp. 560-569.
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