Fusion of the androgen receptor-regulated (AR-regulated) gene with in prostate cancer
Fusion of the androgen receptor-regulated (AR-regulated) gene with in prostate cancer (PCa) causes androgen-stimulated overexpression of ERG, an ETS transcription factor, but critical downstream effectors of ERG-mediating PCa development remain to be established. stimulated, and identify SOX9 as a critical downstream effector of ERG in fusionCpositive PCa. Introduction The androgen receptor (AR) plays a central role in prostate cancer (PCa) development, and its transcriptional functions are partially or fully restored in the tumors that relapse after androgen deprivation therapy (castration-resistant prostate cancer, CRPC) (1). The role of AR in PCa was further strengthened by the discovery of recurrent genomic rearrangements that result in AR-driven overexpression of ETS family transcription factor proto-oncogenes, and in particular the v-ets erythroblastosis virus E26 oncogene homolog, gene and an exon in the Rabbit polyclonal to AP4E1 gene results in androgen-regulated high-level expression of a transcriptionally active, N-terminalCtruncated ERG protein (amino acids 1C44 being deleted in the most common fusion) (2, 3). This fusion is usually an early event, as it is usually found in precursor prostatic intraepithelial neoplasia (PIN) lesions located adjacent to fusionCpositive cancers (4). The fusion gene is usually also highly expressed in CRPC, indicating that overexpressed ERG contributes to PCa development and progression (5). The importance of ERG is usually further supported by studies in the fusionCpositive VCaP cell line, where RNAi-mediated downregulation of ERG impairs cell growth and invasion (6, 7). Moreover, transgenic overexpression of ERG in mouse prostate causes increased proliferation, and in combination with the loss of one PTEN allele, results in PIN or invasive PCa (8C11). Several ERG-regulated genes in fusionCpositive PCa cases Dalcetrapib have been identified, with being one such candidate ERG Dalcetrapib target gene (6, 7, 11C15). Additionally, a recent study found that there was designated overlap between ERG and AR binding sites, and that ERG repressed both AR expression and AR activity on these sites, suggesting that downregulation of AR activity on subsets of genes may be a mechanism of ERG action (12). However, the downstream effectors and functions Dalcetrapib of ERG that drive PCa remain to be firmly established. SOX9 belongs to the SOX (SRY-related HMG box) family of transcription factors and regulates many developmental processes (16, 17). SOX9 mutations cause the disease campomelic dysplasia, which is usually characterized by extreme cartilage and bone malformation, frequent XY sex reversal, and multiple defects in other organs, consistent with an important role in tissue development (18, 19). In the adult, SOX9 contributes to maintenance of stem/progenitor cells in tissues including intestine, liver, pancreas, and hair follicle (20C24), and dysregulated SOX9 expression has been implicated in the pathogenesis of several cancers (25C31). Comparable to AR, SOX9 is usually required for prostate development, and accumulating evidence indicates that it contributes to the development of PCa (32C39). SOX9 in developing prostate is usually expressed by epithelial cells invading into urogenital sinus mesenchyme, and loss of SOX9 causes a serious defect in prostate ductal morphogenesis (33, 35, 36, 39). In adult human prostate, SOX9 is usually normally expressed primarily by the basal cells, which surround the strongly AR-positive luminal epithelium and express only low levels of AR (34). In contrast, SOX9 and AR are coexpressed in PCa cells, with an increased fraction of SOX9-positive cells being found in CRPC and correlating with more aggressive behavior (32, 34). Moreover, a 17q24.3 SNP associated with PCa has been functionally mapped to an enhancer of the gene, and allele-specific recruitment of transcription factors to this enhancer can increase SOX9 and may mediate the increased PCa risk (38). Silencing endogenous SOX9 expression in PCa xenografts by shRNA causes reduced tumor growth, while SOX9 overexpression enhances PCa xenograft growth and invasion (35). Finally, similarly to ERG, transgenic overexpression of SOX9 in mouse prostate epithelium causes hyperplasia, and on a fusionCpositive PCa, and.