The Cistrome and Gene Signature of Androgen Receptor Splice Variants in Castration Resistant Prostate Cancer Cells
| Autor: | Ji Lu, Travis Vander Steen, Farhad Kosari, Lucas P. Nacusi, Haojie Huang, George Vasmatzis, Lucy J. Schmidt, Peter E. Lonergan, Steven P. Balk, George G. Klee, Zhifu Sun, Donald J. Tindall, Liguo Wang, Chunxi Wang, Stephen A. Boorjian |
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| Rok vydání: | 2015 |
| Předmět: |
Male
medicine.medical_specialty medicine.drug_class Urology Biology urologic and male genital diseases Article Androgen deprivation therapy Prostate cancer Internal medicine Tumor Cells Cultured medicine Humans Protein Isoforms splice Alternative splicing High-Throughput Nucleotide Sequencing Gene signature Androgen medicine.disease Gene Expression Regulation Neoplastic Androgen receptor Prostatic Neoplasms Castration-Resistant Endocrinology Cistrome Receptors Androgen Cancer research Transcriptome |
| Zdroj: | Journal of Urology. 193:690-698 |
| ISSN: | 1527-3792 0022-5347 |
| DOI: | 10.1016/j.juro.2014.08.043 |
| Popis: | Spliced variant forms of androgen receptor were recently identified in castration resistant prostate cancer cell lines and clinical samples. We identified the cistrome and gene signature of androgen receptor splice variants in castration resistant prostate cancer cell lines and determined the clinical significance of androgen receptor splice variant regulated genes.The castration resistant prostate cancer cell line 22Rv1, which expresses full-length androgen receptor and androgen receptor splice variants endogenously, was used as the research model. We established 22Rv1-ARFL(-)/ARV(+) and 22Rv1-ARFL(-)/ARV(-) through RNA interference. Chromatin immunoprecipitation coupled with next generation sequencing and microarray techniques were used to identify the cistrome and gene expression profiles of androgen receptor splice variants in the absence of androgen.Androgen receptor splice variant binding sites were identified in 22Rv1-ARFL(-)/ARV(+). A gene set was regulated uniquely by androgen receptor splice variants but not by full-length androgen receptor in the absence of androgen. Integrated analysis revealed that some genes were directly modulated by androgen receptor splice variants. Unsupervised clustering analysis showed that the androgen receptor splice variant gene signature differentiated benign from malignant prostate tissue as well as localized prostate cancer from metastatic castration resistant prostate cancer specimens. Some genes that were modulated uniquely by androgen receptor splice variants also correlated with histological grade and biochemical failure.Androgen receptor splice variants can bind to DNA independent of full-length androgen receptor in the absence of androgen and modulate a unique set of genes that is not regulated by full-length androgen receptor. The androgen receptor splice variant gene signature correlates with disease progression. It distinguishes primary cancer from castration resistant prostate cancer specimens and benign from malignant prostate specimens. |
| Databáze: | OpenAIRE |
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