Metabolomics,Unknown,Transcriptomics,Genomics,Proteomics

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Overexpression of androgen receptor enhances the binding of the receptor to the chromatin in prostate cancer

ABSTRACT: Androgen receptor (AR) is overexpressed in the majority of castration-resistant prostate cancers (CRPCs). Our goal was to study the effect of AR overexpression on the chromatin binding of the receptor and to identify AR target genes that may be important in the emergence of CRPC. We have established two sublines of LNCaP prostate cancer (PC) cell line, one overexpressing AR 2M-bM-^@M-^S3-fold and the other 4M-bM-^@M-^S5-fold compared with the control cells. We used chromatin immunoprecipitation (ChIP) and deep-sequencing (seq) to identify AR-binding sites (ARBSs). We found that the number of ARBSs and the AR-binding strength were positively associated with the level of AR when cells were stimulated with low concentrations of androgens. In cells overexpressing AR, the chromatin binding of the receptor took place in 100-fold lower concentration of the ligand than in control cells. We conM-oM-,M-^Armed the association of AR level and chromatin binding in two PC xenografts, one containing AR gene ampliM-oM-,M-^Acation with high AR expression, and the other with low expression. By combining the ChIP-seq and expression proM-oM-,M-^Aling, we identiM-oM-,M-^Aed AR target genes that are upregulated in PC. Of them, the expression of ZWINT, SKP2 (S-phase kinase-associated protein 2 (p45)) and FEN1 (M-oM-,M-^Bap structure-speciM-oM-,M-^Ac endonuclease 1) was demonstrated to be increased in CRPC, while the expression of SNAI2 was decreased in both PC and CRPC. FEN1 protein expression was also associated with poor prognosis in prostatectomy-treated patients. Finally, the knock-down of FEN1 with small interfering RNA inhibited the growth of LNCaP cells. Our data demonstrate that the overexpression of AR sensitizes the receptor binding to chromatin, thus, explaining how AR signaling pathway is reactivated in CRPC cells. Examination of AR binding with 9 cell line samples + control and 2 xenograft samples + control. ChIPseq with AR antibody in 3 different LNCaP derivative cell lines overexpressing AR upon treatment with different androgen concentrations and 2 different tumor xenografts expressing different AR levels.

ORGANISM(S): Homo sapiens

SUBMITTER: Janne SeppM-CM-$lM-CM-$

PROVIDER: E-GEOD-48308 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Overexpression of androgen receptor enhances the binding of the receptor to the chromatin in prostate cancer.

Urbanucci A A Sahu B B Seppälä J J Larjo A A Latonen L M LM Waltering K K KK Tammela T L J TL Vessella R L RL Lähdesmäki H H Jänne O A OA Visakorpi T T

Oncogene 20110912 17

Androgen receptor (AR) is overexpressed in the majority of castration-resistant prostate cancers (CRPCs). Our goal was to study the effect of AR overexpression on the chromatin binding of the receptor and to identify AR target genes that may be important in the emergence of CRPC. We have established two sublines of LNCaP prostate cancer (PC) cell line, one overexpressing AR 2-3-fold and the other 4-5-fold compared with the control cells. We used chromatin immunoprecipitation (ChIP) and deep-sequ ...[more]

PMID: 21909140

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Project description:Mouse embryonic stem (ES) cells are isolated from the inner cell mass of blastocysts, and can be preserved in vitro in a naive inner-cell-mass-like configuration by providing exogenous stimulation with leukaemia inhibitory factor (LIF) and small molecule inhibition of ERK1/ERK2 and GSK3b signalling (termed 2i/LIF conditions). Hallmarks of naive pluripotency include driving Oct4 (also known as Pou5f1) transcription by its distal enhancer, retaining a pre-inactivation X chromosome state, global reduction in DNA methylation and in H3K27me3 repressive chromatin mark deposition on developmental regulatory gene promoters.Upon withdrawal of 2i/LIF, naM-CM-/ve mouse ES cells can drift towards a primed pluripotent state resembling that of the post-implantation epiblast. Although human ES cells share several molecular features with naive mouse ES cells, they also share a variety of epigenetic properties with primed murine epiblast stem cells (EpiSCs). These include use of the proximal enhancer element to maintain OCT4 expression, pronounced tendency for X chromosome inactivation in most female human ES cells, increase in DNA methylation and prominent deposition of H3K27me3 and bivalency acquisition on lineage regulatory genes. The feasibility for establishing human ground state naive pluripotency in vitro with equivalent molecular and functional features to those characterized in rodent ES cells remains to be defined. Here we establish defined conditions that facilitate the derivation of genetically unmodified human naive pluripotent stem cells from already established primed human ES cells, from somatic cells through induced pluripotent stem (iPS) cell reprogramming or directly from blastocysts. The novel naive pluripotent cells validated herein retain molecular characteristics and functional properties that are highly similar to mouse naive ES cells, and distinct from conventional primed human pluripotent cells. This includes competence in the generation of cross-species chimaeric embryos that underwent organogenesis following microinjection of human naive iPS cells into mouse morulas. Collectively, our findings establish new avenues for regenerative medicine, patient-specific iPS cell disease modelling and the study of early human development in vitro and in vivo. Four chromatin marks H3K4me1, H3K4me3, H3K27ac and H3K27me3 were measured from 3 cell lines: C1 and WIBR3 (naM-CM-/ve and conventional/primed stem cells), and BGO1 (only naM-CM-/ve stem cells).

Dataset Information

Overexpression of androgen receptor enhances the binding of the receptor to the chromatin in prostate cancer

Publications

Overexpression of androgen receptor enhances the binding of the receptor to the chromatin in prostate cancer.

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