Unknown,Transcriptomics,Genomics,Proteomics

Dataset Information

Redefinition of Human Androgen Responsive Elements [FOX_ChIP_exo]

ABSTRACT: The androgen receptor (AR) mediates the action of androgens by binding to androgen-responsive elements (AREs) and subsequently regulating target genes involved in prostate carcinogenesis. The precise locations, true nature, and functional roles of AREs in human prostate cancer are still unknown. Here we redefine AREs by motif-resolution AR chromatin immunoprecipitation-exonuclease (ChIP-exo) assay in human prostate cancer cells and tumors. Surprisingly, we find that, in addition to canonical full-length AREs and half-site-like AREs, a significant portion of the four redefined ARE categories comprises non-canonical full-length AREs. The redefined AREs in enhanced AR binding regions in prostate tumors versus paired non-malignant adjacent tissues regulate a prostate cancer-relevant gene network not only centered on AR, but more interestingly, on novel AR target genes mTOR, BIRC5 and BCL2L1 involved in prostate cancer cell growth and survival. The precise redefinition of AREs has important implications for understanding how AR contributes to prostate carcinogenesis. FOXA1 ChIP-exo

ORGANISM(S): Homo sapiens

SUBMITTER: Xun Lan

PROVIDER: E-GEOD-43678 | biostudies-arrayexpress |

REPOSITORIES: biostudies-arrayexpress

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Publications

Agonist and antagonist switch DNA motifs recognized by human androgen receptor in prostate cancer.

Chen Zhong Z Lan Xun X Thomas-Ahner Jennifer M JM Wu Dayong D Liu Xiangtao X Ye Zhenqing Z Wang Liguo L Sunkel Benjamin B Grenade Cassandra C Chen Junsheng J Zynger Debra L DL Yan Pearlly S PS Huang Jiaoti J Nephew Kenneth P KP Huang Tim H-M TH Lin Shili S Clinton Steven K SK Li Wei W Jin Victor X VX Wang Qianben Q

The EMBO journal 20141222 4

Human transcription factors recognize specific DNA sequence motifs to regulate transcription. It is unknown whether a single transcription factor is able to bind to distinctly different motifs on chromatin, and if so, what determines the usage of specific motifs. By using a motif-resolution chromatin immunoprecipitation-exonuclease (ChIP-exo) approach, we find that agonist-liganded human androgen receptor (AR) and antagonist-liganded AR bind to two distinctly different motifs, leading to distinc ...[more]

PMID: 25535248

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Project description:Androgen receptor (AR) orchestrates an intricate transcriptional regulatory network that governs prostate cancer initiation, development and progression. To understand this network in detail, we generated genome-wide maps of AR occupancy by ChIP-seq in LNCaP cells. We found NKX3-1, an androgen-dependent homeobox protein well-characterized for its role in prostate development and differentiation, being recruited to AR binding sites (ARBS) in response to androgen signaling. We identified 6,359 NKX3-1 binding sites, most of which overlapped with AR. In addition to its novel collaborative transcriptional role at well-known prostate cancer model genes, our binding and knockdown studies further suggested that NKX3-1 potentially regulates AR in a feed-forward manner. Integrative analysis of Oncomine molecular concepts showed that these androgen-regulated AR and NKX3-1 associated genes are significantly overexpressed in prostate carcinoma as well as advanced and recurrent prostate tumors. From our transcriptomic profiling and Gene Ontology analysis, we observed that AR and NKX3-1 co-regulate genes involved in "protein trafficking" processes, which are mandatory events in the integration of oncogenic signaling pathways leading to prostate cancer development and progression. Interestingly, we found that AR and NKX3-1 co-regulate several members of the RAB GTPase family of secretory/trafficking proteins via the involvement of FoxA1 in a ternary complex and we believe that these AR/NKX3-1/FoxA1 co-regulated RAB genes could serve as expression signatures in prostate carcinogenesis. More specifically, through functional analyses, we showed that NKX3-1, together with AR and FoxA1, could promote prostate cancer cell survival through activation of RAB3B expression. Collectively, our study has provided important insights into the hierarchical transcriptional regulatory network established between AR and NKX3-1 and sought to elucidate the important genetic-molecular-phenotypic paradigm in androgen-dependent prostate cancer. Genome-wide binding analyses of AR, NKX3-1 and FoxA1 in LNCaP with or without DHT (5alpha-dihydrotestosterone) stimulation using ChIP-Seq.

Dataset Information

Redefinition of Human Androgen Responsive Elements [FOX_ChIP_exo]

Publications

Agonist and antagonist switch DNA motifs recognized by human androgen receptor in prostate cancer.

Similar Datasets

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