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SIX2 promotes cell plasticity via Wnt/beta-catenin signalling in androgen receptor independent prostate cancer (RNA-seq)

ABSTRACT: The use of androgen receptor (AR) inhibitors in prostate cancer gives rise to increased cellular lineage plasticity resulting resistance to AR-targeted therapies. By examining the chromatin landscape of AR positive prostate cancer cells following exposure to the AR inhibitor enzalutamide, we have identified a novel regulator of cell plasticity, homeobox transcription factor SIX2, whose motif is enriched in accessible regions post-treatment. Our investigation demonstrates that depletion of SIX2 in androgen-independent PC-3 prostate cancer cells is sufficient to induce a switch from a stem-like to an epithelial state, leading to the reduction of key cancer-related properties such as proliferation, colony formation, and metastasis both in vitro and in vivo. These effects are mediated through downregulation of Wnt/β-catenin signalling pathway and subsequent reduced nuclear localization of β-catenin. Collectively, our findings provide compelling evidence that depletion of SIX2 may represent a promising strategy for overcoming cell plasticity mechanisms driving AR resistance in prostate cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235957 | GEO | 2024/03/19

REPOSITORIES: GEO

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SIX2 promotes cell plasticity via Wnt/beta-catenin signalling in androgen receptor independent prostate cancer (ChIP-seq)

Project description:The use of androgen receptor (AR) inhibitors in prostate cancer gives rise to increased cellular lineage plasticity resulting resistance to AR-targeted therapies. By examining the chromatin landscape of AR positive prostate cancer cells following exposure to the AR inhibitor enzalutamide, we have identified a novel regulator of cell plasticity, homeobox transcription factor SIX2, whose motif is enriched in accessible regions post-treatment. Our investigation demonstrates that depletion of SIX2 in androgen-independent PC-3 prostate cancer cells is sufficient to induce a switch from a stem-like to an epithelial state, leading to the reduction of key cancer-related properties such as proliferation, colony formation, and metastasis both in vitro and in vivo. These effects are mediated through downregulation of Wnt/β-catenin signalling pathway and subsequent reduced nuclear localization of β-catenin. Collectively, our findings provide compelling evidence that depletion of SIX2 may represent a promising strategy for overcoming cell plasticity mechanisms driving AR resistance in prostate cancer.

2024-03-19 | GSE235956 | GEO

SIX2 promotes cell plasticity via Wnt/beta-catenin signalling in androgen receptor independent prostate cancer (ATAC-seq)

2024-03-19 | GSE235955 | GEO

Inhibition of Androgen Receptor and β-catenin activity in prostate cancer

Project description:Androgen receptor (AR) is the major therapeutic target in aggressive prostate cancer. However, targeting AR alone can result in drug resistance and disease recurrence. Therefore, simultaneous targeting of multiple pathways could in principle be an effective new approach to treating prostate cancer. Here we provide proof-of-concept that a small molecule inhibitor of nuclear β-catenin activity (called C3) can inhibit both the AR and β-catenin signaling pathways that are often misregulated in prostate cancer. Treatment with C3 ablated prostate cancer cell growth by disruption of both β-catenin/TCF and β-catenin/AR protein interaction, reflecting the fact that TCF and AR have overlapping binding sites on β-catenin. Given that AR interacts with, and is transcriptionally regulated by β-catenin, C3 treatment also resulted in decreased occupancy of β-catenin on the AR promoter and diminished AR and AR/β-catenin target gene expression. Interestingly, C3 treatment resulted in decreased AR binding to target genes accompanied by decreased recruitment of an AR and β-catenin cofactor, CARM1, providing new insight into the unrecognized function of β-catenin in prostate cancer. Importantly, C3 inhibited tumor growth in an in vivo xenograft model, and blocked renewal of bicalutamide-resistant sphere forming cells, indicating the therapeutic potential of this approach. Compare and contrast the expression profile of prostate cancer cells treated with a Wnt inhibitor (C3) with respect to β-catenin and AR knockdown (all samples in duplicates).

2014-01-23 | E-GEOD-49295 | biostudies-arrayexpress

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Transcription profiling of human prostate cancer cell lines after androgen depletion and AR knock-down

Project description:Although the vital role of the androgen receptor (AR) has been well demonstrated in primary prostate cancers, its role in the androgen-insensitive prostate cancers still remains unclear. Here, we used a small hairpin RNA approach to directly assess AR activity in prostate cancer cells. Reduction of AR expression in the two androgen-sensitive prostate cancer cell lines, LNCaP and LAPC4, significantly decreased AR-mediated transcription and cell growth. Intriguingly, in two androgen-insensitive prostate cell lines, LNCaP-C42B4 and CWR22Rv1, knockdown of AR expression showed a more pronounced effect on AR-induced transcription and cell growth than androgen depletion. Using cDNA microarrays, we also compared the transcriptional profiles induced by either androgen depletion or AR knockdown. Although a significant number of transcripts appear to be regulated by both androgen depletion and AR knockdown, we observed a subset of transcripts affected only by androgen depletion but not by AR knockdown, and vice versa. Finally, we demonstrated a direct role for AR in promoting tumor formation and growth in a xenograft model. Taken together, our results elucidate an important role for the AR in androgen-insensitive prostate cancer cells, and suggest that AR can be used as a therapeutic target for androgen-insensitive prostate cancers.

2007-05-04 | E-SMDB-4028 | biostudies-arrayexpress

Transcriptional profiles induced by either androgen depletion or androgen receptor knockdown

2007-08-08 | E-GEOD-7585 | biostudies-arrayexpress

Genome-wide maps of Six2 and b-catenin in mesenchymal nephron progenitors

Project description:Self-renewing undifferentiated nephron progenitors express Six2, a transcription factor that is required for their maintenance as undifferentiated progenitors. Differentiation of nephron progenitors is triggered by Wnt/b-catenin signaling. In order to understand how Six2 and Wnt signaling counteract each other, we performed ChIP-seq of Six2 and b-catenin in mesenchymal nephron progenitor cells. Nephron progenitors were FACS-isolated from BAC transgenic Six2GFPcre-positive embryonic kidneys at E16.5. For Six2 ChIP, freshly FACS isolated Six2+ cells were used. For b-catenin ChIP, FACS isolated Six2+ cells were aggregated by centrifugation at 850g for 5min and incubated in 10%FBS/DMEM containing 4uM BIO for 24hrs.

2012-09-11 | E-GEOD-39837 | biostudies-arrayexpress

ANDROGEN RECEPTOR WITH SHORT POLYGLUTAMINE TRACT PREFERABLY ENHANCES WNT/BETA-CATENIN MEDIATED PROSTATE TUMORIGENESIS

Project description:Polyglutamine (polyQ) tract polymorphism within the human androgen receptor (AR) shows population heterogeneity. African American men possess short polyQ tracts significantly more frequently than Caucasian American men. The length of polyQ tracts is inversely correlated with the risk of prostate cancer, age of onset, and aggressiveness at diagnosis. Aberrant activation of Wnt signaling also reveals frequently in advanced prostate cancer, and an enrichment of androgen and Wnt signaling activation has been observed in African American patients. Here, we investigated aberrant expression of AR bearing different polyQ tracts and stabilized β-catenin in prostate tumorigenesis using newly generated mouse models. We observed an early onset oncogenic transformation, accelerated tumor cell growth, and aggressive tumor phenotypes in the compound mice bearing short polyQ tract AR and stabilized β-catenin. RNA sequencing analysis showed a robust enrichment of Myc-regulated downstream genes in tumor samples bearing short polyQ AR versus those with longer polyQ tract AR. Upstream regulator analysis further identified Myc as the top candidate of transcriptional regulators in tumor cells from the above mouse samples with short polyQ tract AR and β-catenin. Chromatin immunoprecipitation analyses revealed increased recruitment of b-catenin and AR on the c-Myc gene regulatory locus in the tumor tissues expressing stabilized b-catenin and shorter polyQ tract AR. These data demonstrate a promotional role of aberrant activation of Wnt/b-catenin in combination with short polyQ AR expression in prostate tumorigenesis and provide mechanistic insight into aggressive prostatic tumor development that is frequently observed in African American patients.

2020-03-31 | GSE140963 | GEO

Transcriptional profiles induced by either androgen depletion or androgen receptor knockdown

2007-08-09 | GSE7585 | GEO

DPYSL5 is Highly Expressed in treatment-induced Neuroendocrine Prostate Cancer and Promotes Lineage Plasticity via EZH2/PRC2

Project description:Treatment-induced neuroendocrine prostate cancer (t-NEPC) is a lethal subtype of castration-resistant prostate cancer resistant to androgen receptor (AR) inhibitors. Our study unveils that AR suppresses neuronal development protein dihydropyrimidinase-related protein 5 (DPYSL5), providing a mechanism for neuroendocrine transformation under androgen deprivation therapy. Our unique CRPC-NEPC cohort with 157 patient samples, including 55 t-NEPC patient samples, shows a high expression of DPYSL5 in t-NEPC patients, and that DPYSL5 correlates with neuroendocrine markers and inversely with AR and PSA. DPYSL5 overexpression in prostate cancer cells induces neuron like phenotype, enhances invasion, proliferation, and upregulates stemness and neuroendocrine related markers. Mechanistically, DPYSL5 promotes prostate cancer cell plasticity via EZH2-mediated PRC2 activation. Depletion of DPYSL5 halts proliferation, induces G1 phase cell cycle arrest, reverses neuroendocrine phenotype and upregulates luminal genes. In conclusion, DPYSL5 plays a critical role in regulating prostate cancer cell plasticity, and we propose the AR/DPYSL5/EZH2/PRC2 axis as a novel driver of t-NEPC progression.

2024-01-02 | GSE151433 | GEO

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