Interplay of DNA Methylation and Histone Methylation Driving Neuroendocrine Phenotype in Advanced Prostate Cancer
Abstract
Project: Interplay of DNA Methylation and Histone Methylation Driving Neuroendocrine Phenotype in Advanced Prostate Cancer Background and Rationale: Castration-resistant prostate cancer with neuroendocrine features (NEPC) is characterized by androgen-independence, androgen receptor (AR)-negative, loss of luminal identity, expression of neural markers, and poorly differentiated tumors, unlike CRPC, which is AR-high, expression of luminal markers, and adenocarcinoma histology. While there is substantial overlap in genomic alterations between NEPC and CRPC, epigenetic alterations (including the DNA methylome differences) and expression profiles of patients of two subtypes are quite unique segregating them into two clusters. These results suggest clonal evolution of NEPC from CRPC and points to the possible importance of epigenetic regulation in this transition. Despite advances in the development of highly effective AR-targeted therapies for the treatment of men with advanced prostate cancer, acquired resistance ultimately ensues. Dissecting the underlying epigenetic changes driving the progression of these subtypes, which often arise as a result of anti-androgen treatment, remains an unmet clinical need for the development of treatment for these subtypes, especially the small cell neuroendocrine prostate cancer, which has an even worse prognosis. We and others previously identified NMyc as a key driver of the progression from CRPC towards NEPC. Changes in NMyc-directed epigenomic reprogramming is androgen-dependent and drives a lineage switch in prostate cancer epithelial toward a neural identity that favors the development of AR independence and NEPC. Loss of the tumor suppressors, TP53 and Rb1, and upregulation of EZH2 (PRC2 component, marks genes with repressive H3K27me3 marks) have also been associated with the development of AR-indifferent prostate cancer. Recent data from novel genetically engineered mouse models (GEMs) from our laboratory suggest that MYCN overexpression synergizes with Rb1 loss to drive metastatic prostate cancer and establish a molecular program (transcriptome and methylome) that mimics clinical NEPC tumors. Interaction of DNA methylation and repressive H3K27me3 or active H3K4me3 marks have been well elucidated in embryonic stem cells and cancer cell lines. DNMTs, DNA methylation writers and TET1, DNA methylation erasers were overexpressed in NEPC compared to CRPC patient samples like in our GEM models. However, a detailed understanding of change in methylome and its interaction with histone marks leading to transition of CRPCs toward neural lineage is still lacking. Hypothesis and Specific Aims: Based on published data from clinical samples and preliminary study on our models, we hypothesize that DNA methylation plays an important role in driving the progression of CRPC toward NEPC. Some of these changes in DNA methylome may act in concert with histone repressive and activation marks to set the stage for change in lineage of cancer cells. The long-term goal of our study is to understand the interplay of these epigenetic changes that drive the transition of advanced prostate cancer toward neural identity for better therapeutic interventions. To address our hypothesis, we have planned this study with following aims: Aim 1. Characterize temporal change in DNA methylome (at a single-cell resolution) and binding profile of DNA methylation regulators. Compare with a single-cell expression profile in our murine models with NMyc overexpression and Rb1/Rb1 and EZH2 loss. Aim 2. Characterize the temporal relationship between DNA methylation and repressive or active histone marks in same murine models. Compare the change in methylome and histone mark profile upon knockdown of DNMTs/TET1/EZH2 in mouse and human organoids grown in vivo in mouse. Aim 3. Assess the therapeutic potential of DNMT/TET1 inhibition with/without EZH2 inhibition on tumor growth and the metastatic po
Document Details
- Document Type
- DoD Grant Award
- Publication Date
- Dec 05, 2021
- Source ID
- W81XWH2110090
Entities
People
- Richa Singh
Organizations
- United States Army
- Weill Cornell Medicine