The pluripotency factor Nanog is directly upregulated by the Androgen Receptor in prostate cancer cells

Abstract

Background The Androgen Receptor (AR) is a nuclear hormone receptor that functions as a critical oncogene in all stages of prostate cancer progression, including progression to castration-resistance following androgen-deprivation therapy. Thus, identifying and targeting critical AR-regulated genes is one potential method to block castration-resistant cancer proliferation. Of particular importance are transcription factors that regulate stem cell pluripotency; many of these genes are emerging as critical oncogenes in numerous tumor cell types. Of these, Nanog has been previously shown to increase the self-renewal and stem-like properties of prostate cancer cells. Thus, we hypothesized that Nanog is a candidate AR target gene that may impart castration-resistance. Methods We modulated AR signaling in LNCaP prostate cancer cells and assayed for Nanog expression. Direct AR binding to the NANOG promoter was tested using AR Chromatin Immunoprecipation (ChIP) and analyses of publically available AR ChIP-sequencing data-sets. Nanog over-expressing cells were analyzed for cell growth and cytotoxicity in response to the AR antagonist enzalutamide and the microtubule stabilizing agent docetaxel. Results AR signaling upregulates Nanog mRNA and protein. AR binds directly to the NANOG promoter, and was not identified within 75kb of the NANOGP8 pseudogene, suggesting the NANOG gene locus was preferentially activated. Nanog overexpression in LNCaP cells increases overall growth, but does not increase resistance to enzalutamide or docetaxel. Conclusions Nanog is a novel oncogenic AR target gene in prostate cancer cells, and stable expression of Nanog increases proliferation and growth of prostate cancer cells, but not resistance to enzalutamide or docetaxel.

Regulation of tumor cell plasticity by the androgen receptor in prostate cancer

“…For example, SOX2 is transcriptionally repressed by AR, and, as expected, treating multiple PCa cell lines with the antiandrogen enzalutamide has been shown to increase SOX2 expression and to lead to CRPC tumor formation (Kregel et al 2013). AR has also been reported to directly bind to the NANOG promoter (Kregel et al 2014) to impart castration resistance in LNCaP cells driven by the expansion of CD133 C and ALDH1 C CSCs (Jeter et al 2011). Apart from direct transcriptional regulation, AR can also indirectly modulate the Wnt (Bisson & Prowse 2009), PI3K/AKT (Dubrovska et al 2009), and hedgehog (Gowda et al 2013) signaling cascades, which play an important role in regulating PCa CSC self-renewal.…”

Androgen/androgen receptor axis maintains and promotes cancer cell stemness through direct activation of Nanog transcription in hepatocellular carcinoma

“…And it has been reported that androgen could increase Nanog expression in prostate cancer [19]. These data inspired us to wonder whether the effect of androgen/AR axis on stemness of HCC cells was Nanog depended.…”

NANOG reprograms prostate cancer cells to castration resistance via dynamically repressing and engaging the AR/FOXA1 signaling axis

“…We have further identified multiple E-box elements upstream of NP8 (−133, −486, −1 301, −1 343, −1 437 and −1 607 bp relative to the TSS [1]), suggesting that MYC and NANOG may also form a feed forward cross-regulatory loop. Finally, potential interactions in tumors among AR, NANOG and other pluripotency regulators such as SOX2 (for example, SOX2 has been implicated as an AR-repressed gene that contributes to CRPC [44] and AR has been reported to induce NANOG [45]) may well alter the landscape of the reprogramming dynamics. Future work will aim to elucidate these complicated NANOG interactions and the epigenetic mechanisms whereby NANOG maintains the CSC state.…”