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

ABSTRACT: This SuperSeries is composed of the SubSeries listed below.

ORGANISM(S): Homo sapiens

PROVIDER: GSE235958 | 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 (RNA-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 | GSE235957 | GEO

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

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

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

Project description:SIX2 promotes cell plasticity via Wnt/beta-catenin signalling in androgen receptor independent prostate cancer

| PRJNA988079 | ENA

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

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

| PRJNA988086 | ENA

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

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

| PRJNA988085 | ENA

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

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

| PRJNA988089 | ENA

The Androgen Receptor Antagonizes Wnt/β-Catenin Signaling in Epidermal Stem Cells.

Project description:Activation of Wnt/β-catenin signaling in adult mouse epidermis leads to expansion of the stem cell compartment and redirects keratinocytes in the interfollicular epidermis and sebaceous glands (SGs) to differentiate along the hair follicle (HF) lineages. Here we demonstrate that during epidermal development and homeostasis there is reciprocal activation of the androgen receptor (AR) and β-catenin in cells of the HF bulb. AR activation reduced β-catenin-dependent transcription, blocked β-catenin-induced induction of HF growth, and prevented β-catenin-mediated conversion of SGs into HFs. Conversely, AR inhibition enhanced the effects of β-catenin activation, promoting HF proliferation and differentiation, culminating in the formation of benign HF tumors and a complete loss of SG identity. We conclude that AR signaling has a key role in epidermal stem cell fate selection by modulating responses to β-catenin in adult mouse skin.

| S-EPMC4641324 | biostudies-literature

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

Androgen receptor with short polyglutamine tract preferably enhances Wnt/β-catenin-mediated prostatic 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 assessed 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 β-catenin and AR on the c-Myc gene regulatory locus in the tumor tissues expressing stabilized β-catenin and shorter polyQ tract AR. These data demonstrate a promotional role of aberrant activation of Wnt/β-catenin in combination with short polyQ AR expression in prostate tumorigenesis and suggest a potential mechanism underlying aggressive prostatic tumor development, which has been frequently observed in African American patients.

| S-EPMC7165053 | biostudies-literature

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