title: Differentially methylated genes and androgen receptor re-expression in small cell prostate carcinomas.
abstract: Small cell prostate carcinoma (SCPC) morphology is rare at initial diagnosis but often emerges during prostate cancer progression and portends a dismal prognosis. It does not express androgen receptor (AR) or respond to hormonal therapies. Clinically applicable markers for its early detection and treatment with effective chemotherapy are needed. Our studies in patient tumor-derived xenografts (PDX) revealed that AR-negative SCPC (AR(-)SCPC) expresses neural development genes instead of the prostate luminal epithelial genes characteristic of AR-positive castration-resistant adenocarcinomas (AR(+)ADENO). We hypothesized that the differences in cellular lineage programs are reflected in distinct epigenetic profiles. To address this hypothesis, we compared the DNA methylation profiles of AR(-) and AR(+) PDX using methylated CpG island amplification and microarray (MCAM) analysis and identified a set of differentially methylated promoters, validated in PDX and corresponding donor patient samples. We used the Illumina 450K platform to examine additional regions of the genome and the correlation between the DNA methylation profiles of the PDX and their corresponding patient tumors. Struck by the low frequency of AR promoter methylation in the AR(-)SCPC, we investigated this region's specific histone modification patterns by chromatin immunoprecipitation. We found that the AR promoter was enriched in silencing histone modifications (H3K27me3 and H3K9me2) and that EZH2 inhibition with 3-deazaneplanocin A (DZNep) resulted in AR expression and growth inhibition in AR(-)SCPC cell lines. We conclude that the epigenome of AR(-) is distinct from that of AR(+) castration-resistant prostate carcinomas, and that the AR(-) phenotype can be reversed with epigenetic drugs.
authors.affiliation: a Department of Genitourinary Medical Oncology Unit 1374 , The University of Texas MD Anderson Cancer Center , 1515 Holcombe Blvd., Houston , Texas.
authors.forename: Brittany
authors.initials: B
authors.lastname: Kleb
authors.affiliation: b Department of Epigenetics and Molecular Carcinogenesis , Unit 0081, The University of Texas, MD Anderson Cancer Center , 1515 Holcombe Blvd., Houston , Texas.
authors.forename: Marcos R H
authors.initials: MR
authors.lastname: Estécio
authors.affiliation: c Department of Bioinformatics and Computational Biology , Unit 1410, The University of Texas MD Anderson Cancer Center , 1515 Holcombe Blvd., Houston , Texas.
authors.forename: Jiexin
authors.initials: J
authors.lastname: Zhang
authors.affiliation: d Department of Pathology , University of Patras, Panepistimioupoli Patron , Greece.
authors.forename: Vassiliki
authors.initials: V
authors.lastname: Tzelepi
authors.affiliation: e Fels Institute of Cancer Research and Molecular Biology, Temple University , 3307 N Broad Street, Philadelphia , PA.
authors.forename: Woonbok
authors.initials: W
authors.lastname: Chung
authors.affiliation: e Fels Institute of Cancer Research and Molecular Biology, Temple University , 3307 N Broad Street, Philadelphia , PA.
authors.forename: Jaroslav
authors.initials: J
authors.lastname: Jelinek
authors.affiliation: f Department of Genitourinary Medical Oncology , Unit 1374, The University of Texas MD Anderson Cancer Center , 1515 Holcombe Blvd., Houston , Texas.
authors.forename: Nora M
authors.initials: NM
authors.lastname: Navone
authors.affiliation: f Department of Genitourinary Medical Oncology , Unit 1374, The University of Texas MD Anderson Cancer Center , 1515 Holcombe Blvd., Houston , Texas.
authors.forename: Salahaldin
authors.initials: S
authors.lastname: Tahir
authors.affiliation: g Center for Cancer Research, National Cancer Institute, Building 376 Frederick , MD.
authors.forename: Victor E
authors.initials: VE
authors.lastname: Marquez
authors.affiliation: e Fels Institute of Cancer Research and Molecular Biology, Temple University , 3307 N Broad Street, Philadelphia , PA.
authors.forename: Jean-Pierre
authors.initials: JP
authors.lastname: Issa
authors.affiliation: f Department of Genitourinary Medical Oncology , Unit 1374, The University of Texas MD Anderson Cancer Center , 1515 Holcombe Blvd., Houston , Texas.
authors.forename: Sankar
authors.initials: S
authors.lastname: Maity
authors.affiliation: f Department of Genitourinary Medical Oncology , Unit 1374, The University of Texas MD Anderson Cancer Center , 1515 Holcombe Blvd., Houston , Texas.
authors.forename: Ana
authors.initials: A
authors.lastname: Aparicio
mesh_terms: D000241:Adenosine / Q000008:administration & dosage / Q000031:analogs & derivatives; D000818:Animals; D018288:Carcinoma, Small Cell / Q000235:genetics* / Q000473:pathology; D045744:Cell Line, Tumor; D019070:Cell Lineage / Q000235:genetics; D018899:CpG Islands / Q000235:genetics; D019175:DNA Methylation / Q000235:genetics*; D000071221:Enhancer of Zeste Homolog 2 Protein / Q000037:antagonists & inhibitors / Q000235:genetics*; D015972:Gene Expression Regulation, Neoplastic / Q000187:drug effects; D006801:Humans; D008297:Male; D051379:Mice; D011401:Promoter Regions, Genetic; D064129:Prostatic Neoplasms, Castration-Resistant / Q000235:genetics* / Q000473:pathology; D011944:Receptors, Androgen / Q000096:biosynthesis / Q000235:genetics*; D023041:Xenograft Model Antitumor Assays
chemical_list: D011944:Receptors, Androgen; C048460:3-deazaneplanocin; C498409:EZH2 protein, human; D000071221:Enhancer of Zeste Homolog 2 Protein; D000241:Adenosine
keywords: Androgen receptor; DNA methylation; EZH2; epigenetics; histone methylation; neuroendocrine; prostate cancer; small-cell prostate carcinoma; xenograft