Dissertation/Thesis Abstract

Epigenetic regulation by MYC: Oncogene-mediated changes in H3K27ME3 in prostate cancer
by Slider, Laxmi G. Pellakuru, Ph.D., The Johns Hopkins University, 2013, 192; 3573099
Abstract (Summary)

Prostate cancer is one of the most commonly diagnosed cancers in the United States. The MYC oncogene has been shown to play an important role in the initiation and progression of prostate carcinoma. In mouse models of MYC-induced prostate adenocarcinoma, MYC activation simultaneously coincides with massive changes in chromatin structure leading to a more open chromatin conformation—a classic characteristic of cancers.

In this work, we study such epigenetic alterations by focusing on analyzing levels of the Polycomb heterochromatin mark, H3K27me3. We also examine the correlation between H3K27me3 and its histone methyltransferase, EZH2, a Polycomb component, in numerous tissues including prostate. We find that H3K27me3 levels decrease in prostate cancer, and furthermore, in normal tissues with hierarchical organization, H3K27me3 levels directly track with differentiation. We also show that MYC levels affect the global level of H3K27me3 as well as its genomic distribution; as a result of MYC knockdown, there is a three-fold increase in the number of H3K27me3 binding sites especially in intergenic regions. With high levels of MYC expression, we also find that a significant number of sites, mostly close to transcription start sites, are triple marked with MYC, EZH2, and H3K27me3.

Additionally, we observe that both H3K27me3 and the DNA modification, 5-hydroxymethycytosine, track with differentiation in normal tissues, and both epigenetic marks are decreased in numerous cancers compared to normal tissues. Furthermore, we observed that another Polycomb component, BMI, shows no differential expression between stem-like basal cells and luminal cells in the prostate and has decreased expression in primary prostate carcinoma. As such, BMI1 cannot serve as a marker of prostate stem cells or cancer.

Overall, by focusing on the Polycomb repressive mark, H3K27me3, we show that the global levels of this mark are decreased in prostate and other cancers early in the disease process, and one mechanism responsible for this decrease is likely MYC overexpression. It is evident that understanding the molecular mechanisms driving the development and progression of prostatic carcinoma requires a grasp of both epigenetic as well as genetic alterations and such knowledge may ultimately lead to better therapies as well as methods of prevention.

Indexing (document details)
Advisor: Marzo, Angelo M. De
School: The Johns Hopkins University
School Location: United States -- Maryland
Source: DAI-B 74/12(E), Dissertation Abstracts International
Subjects: Molecular biology, Cellular biology, Medicine, Oncology
Keywords: Epigenetic regulation, H3K27ME3, MYC, Polycomb, Prostate cancer
Publication Number: 3573099
ISBN: 9781303422669
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