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.
Highlights
NK3 homeobox 1 (Nkx3.1), a transcription factor expressed in the prostate epithelium, is crucial for maintaining prostate cell fate and suppressing tumor initiation
We show that the 11-kb region 3Ј to the Nkx3.1 transcription start site (TSS) is responsible for Nkx3.1 expression alterations in adult prostate under various physiological conditions (Fig. 4F)
The 11-kb transgene was able to recapitulate the normal Nkx3.1 expression pattern in adult prostate and induce the same levels of expression as the previously characterized 32-kb and 17-kb transgenes [4], suggesting that the 5Ј sequence of the Nkx3.1 locus is dispensable for this purpose
Summary
NK3 homeobox 1 (Nkx3.1), a transcription factor expressed in the prostate epithelium, is crucial for maintaining prostate cell fate and suppressing tumor initiation. How CARNs are specified is unclear; the retention of their Nkx3.1 expression could be due to an intrinsically different cellular program from other luminal cells or, alternatively, stochastically determined by the local microenvironment Another important question concerning Nkx3.1 expression arises from studies of prostate cancer. Under prostate tumor– initiating conditions, such as the loss of Pten, luminal Nkx3.1 expression is abolished in both human samples and mouse models (19 –22) A pioneer study using transgenic LacZ reporter mice discovered that a 32-kb fragment containing 20 kb upstream and 12 kb downstream of the Nkx3.1 transcription start site (TSS) could drive the endogenous Nkx3.1 expression pattern in most organs during embryogenesis [4] Within this fragment, the downstream-most 5-kb region acted as a urogenital enhancer that partially restored prostatic Nkx3.1 expression [4].
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