The Epigenetics of Small Cell Prostate Cancer

<p>Small cell prostate cancer (SCPC) is an androgen receptor (AR) negative variant that can develop during the progression of castration-resistant AR-positive (AR⁺) prostate adenocarcinomas. While rare at initial diagnosis, SCPC is present in 10-20% of patients resulting in an aggressive clinical course with poor response to hormonal therapies and a short median survival. Our studies in patient-tumor derived xenografts revealed that the AR-negative small cell prostate carcinomas (AR^-SCPC) express genes involved in neural development instead of the prostate luminal epithelial gene expression that characterizes AR-positive castration-resistant adenocarcinomas (AR⁺ADENO). We hypothesized that the differences in cellular lineage programs should be reflected in distinct epigenetic profiles and that they could be reversed with epigenetic drugs. Using Methylated CpG Amplification coupled to Microarray (MCAM) we identified distinctly hypermethylated DNA sequences present in AR^-SCPC but not in AR⁺ADENO xenografts. Interestingly, we observed a low frequency of AR promoter methylation found in samples that lacked AR expression despite previous publications, which led to further analysis of possible silencing mechanisms. Using ChIP-qPCR, we found that the AR promoter is enriched in silencing histone modifications (H3K27me3 and H3K9me2) and that EZH2 inhibition with DZNep results in AR re-expression and growth inhibition in AR^-SCPC cell lines. These data support the hypothesis that AR^-SCPC are epigenetically distinct from AR⁺ADENO tumors and that epigenetic therapies may reverse the AR^-SCPC phenotype.</p>

Name thesis:degree_name

Masters of Science (MS)

Level thesis:degree_level

Thesis (MS)

Year dc:date.available

2014

Author dc:creator

• Kleb, Brittany N

Contributors dc:contributor

• Ana Aparicio, MD
• Marcos Estecio, PhD
• Elsa Flores, PhD

• castrate-resistant prostate cancer
• small cell prostate cancer
• DNA methylation profiling
• methylome
• histone modifications
• EZH2
• androgen receptor
• epigenetics
• PRC2
• DZNep
• Biology

Repository record dc:identifier

https://digitalcommons.library.tmc.edu/utgsbs_dissertations/470

OAI identifier oai:identifier

oai:digitalcommons.library.tmc.edu:utgsbs_dissertations-1509