Presentation Abstract

Abstract Number: 2210
Presentation Title: Global levels of H3K27me3 track with differentiation in vivo and are deregulated by MYC in prostate cancer
Presentation Time: Monday, Apr 02, 2012, 1:00 PM - 5:00 PM
Location: McCormick Place West (Hall F), Poster Section 8
Poster Section: 8
Poster Board Number: 14
Author Block: Laxmi Gurunatham Pellakuru, Tsuyoshi Iwata, Bora Gurel, Angelo M. De Marzo. Johns Hopkins University, Baltimore, MD
Abstract Body: Both embryonic stem cells and various cancer cell types contain abundant amounts of decondensed chromatin. However, the molecular mechanisms responsible for altering chromatin states in stem cells and cancer cells are not well understood. One factor may be the oncogenic transcription factor, MYC. MYC is overexpressed in many tumor types and affects a wide array of essential cellular processes including ribosome and mitochondrial biogenesis, metabolism, and cell cycle progression. MYC is also a key factor in reprogramming of somatic adult cells into induced pluripotent stem cells. Less well known is that MYC also affects global chromatin structure where it is required to maintain open or active chromatin. We hypothesize that in prostate cancer, MYC affects global chromatin structure keeping it in a more open conformation thus maintaining the cells in a less differentiated state resembling that of stem cells.
We show by immunohistochemistry that compared to the more differentiated luminal cells, less differentiated stem-like cells in the basal compartment of the human and mouse prostate contain lower levels of the polycomb heterochromatin mark, H3K27me3. This link to the differentiated state of normal cells is also found in a number of other human and rodent tissues characterized by hierarchical differentiation and rapid turnover of stem cell compartments. Further, in MYC-driven prostate cancers in mice, global levels of H3K27me3 are reduced in both prostatic intraepithelial neoplasia (PIN) and invasive adenocarcinoma lesions. This pattern of global H3K27me3 reduction in PIN and invasive prostate cancers is also observed in humans, correlates with global chromatin decondensation, and correlates with increased markers of disease aggressiveness (e.g. Gleason score and pathological stage). In prostate and breast cancer cells, experimentally forced reductions in MYC levels result in increased global levels of H3K27me3. These findings suggest that increased levels of decondensed chromatin in normal stem/progenitor cells and in cancer cells are associated with global loss of the H3K27me3 polycomb mark, and furthermore, MYC overexpression could be one mechanism for this H3K27me3 deregulation.