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Transcriptional regulation of the Nkx3.1 gene in prostate luminal stem cell specification and cancer initiation via its 3' genomic region.

ABSTRACT: NK3 homeobox 1 (Nkx3.1), a transcription factor expressed in the prostate epithelium, is crucial for maintaining prostate cell fate and suppressing tumor initiation. Nkx3.1 is ubiquitously expressed in luminal cells of hormonally intact prostate but, upon androgen deprivation, exclusively labels a type of luminal stem cells named castration-resistant Nkx3.1-expressing cells (CARNs). During prostate cancer initiation, Nkx3.1 expression is frequently lost in both humans and mouse models. Therefore, investigating how Nkx3.1 expression is regulated in vivo is important for understanding the mechanisms of prostate stem cell specification and cancer initiation. Here, using a transgenic mouse line with destabilized GFP, we identified an 11-kb genomic region 3' of the Nkx3.1 transcription start site to be responsible for alterations in Nkx3.1 expression patterns under various physiological conditions. We found that androgen cell-autonomously activates Nkx3.1 expression through androgen receptor (AR) binding to the 11-kb region in both normal luminal cells and CARNs and discovered new androgen response elements in the Nkx3.1 3' UTR. In contrast, we found that, in Pten-/- prostate tumors, loss of Nkx3.1 expression is mediated at the transcriptional level through the 11-kb region despite functional AR in the nucleus. Importantly, the GFP reporter specifically labeled CARNs in the regressed prostate only in the presence of cell-autonomous AR, supporting a facultative model for CARN specification.

SUBMITTER: Xie Q

PROVIDER: S-EPMC5566512 | biostudies-other | 2017 Aug

REPOSITORIES: biostudies-other

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Transcriptional regulation of the <i>Nkx3.1</i> gene in prostate luminal stem cell specification and cancer initiation via its 3' genomic region.

Xie Qing Q Wang Zhu A ZA

The Journal of biological chemistry 20170705 33

NK3 homeobox 1 (Nkx3.1), a transcription factor expressed in the prostate epithelium, is crucial for maintaining prostate cell fate and suppressing tumor initiation. Nkx3.1 is ubiquitously expressed in luminal cells of hormonally intact prostate but, upon androgen deprivation, exclusively labels a type of luminal stem cells named castration-resistant Nkx3.1-expressing cells (CARNs). During prostate cancer initiation, Nkx3.1 expression is frequently lost in both humans and mouse models. Therefore ...[more]

PMID: 28679531

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Project description:Genomic islands (GIs), frequently associated with the pathogenicity of bacteria and having a substantial influence on bacterial evolution, are groups of "alien" elements which probably undergo special temporal-spatial regulation in the host genome. Are there particular hallmark transcriptional signals for these "exotic" regions? We here explore the potential transcriptional signals that underline the GIs beyond the conventional views on basic sequence composition, such as codon usage and GC property bias. It showed that there is a significant enrichment of the transcription start positions (TSPs) in the GI regions compared to the whole genome of Salmonella enterica and Escherichia coli. There was up to a four-fold increase for the 70% GIs, implying high-density TSPs profile can potentially differentiate the GI regions. Based on this feature, we developed a new sliding window method GIST, Genomic-island Identification by Signals of Transcription, to identify these regions. Subsequently, we compared the known GI-associated features of the GIs detected by GIST and by the existing method Islandviewer to those of the whole genome. Our method demonstrates high sensitivity in detecting GIs harboring genes with biased GI-like function, preferred subcellular localization, skewed GC property, shorter gene length and biased "non-optimal" codon usage. The special transcriptional signals discovered here may contribute to the coordinate expression regulation of foreign genes. Finally, by using GIST, we detected many interesting GIs in the 2011 German E. coli O104:H4 outbreak strain TY-2482, including the microcin H47 system and gene cluster ycgXEFZ-ymgABC that activates the production of biofilm matrix. The aforesaid findings highlight the power of GIST to predict GIs with distinct intrinsic features to the genome. The heterogeneity of cumulative TSPs profiles may not only be a better identity for "alien" regions, but also provide hints to the special evolutionary course and transcriptional regulation of GI regions.

Dataset Information

Transcriptional regulation of the Nkx3.1 gene in prostate luminal stem cell specification and cancer initiation via its 3' genomic region.

Publications

Transcriptional regulation of the <i>Nkx3.1</i> gene in prostate luminal stem cell specification and cancer initiation via its 3' genomic region.

Similar Datasets

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