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Expression data and H3K27me3 occupancy profiling by high throughput sequencing from control and SETD2 knockout organoids cells.

ABSTRACT: To understand the molecular basis how Setd2 loss enhances metastatic traits of PCa, we carried out RNA-seq and H3k27me3 Chip-seq using mice-derived prostatic organoid cells from 3-month-old PtenPC+/− and PtenPC+/−;Setd2PC−/− mice.To further validate Setd2 loss accelerated prostate tumorigenesis is dependent on EZH2 upregulation,we conduct high throughput sequencing of organoid cells derived from PtenPC+/− and PtenPC+/−;Setd2PC−/− mice with Ezh2 knockout.To understand the molecular basis whether the tumor suppressive function of Setd2 is depends on its methylation of EZH2 at k735, we also carried out RNA-seq using mice-derived prostatic organoid cells from 2-month-old PtenPC-/- and PtenPC-/-;Ezh2K735R mice.We integrated all the RNA-seq and chip-seq data generated from organoid cells.

ORGANISM(S): Mus musculus

PROVIDER: GSE136830 | GEO | 2020/12/22

REPOSITORIES: GEO

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Project description:Castration-resistant prostate cancer is a lethal disease. The cell type(s) that survive androgen-deprivation remain poorly described despite global efforts to understand the various mechanisms of therapy resistance. We recently identified in wild type mouse prostates a rare population of luminal progenitor cells that we called LSCmed according to their FACS profile (Lin?/Sca-1+/CD49fmed). Here we investigated the prevalence and castration resistance of LSCmed in various mouse models of prostate tumorigenesis. In intact mice, we show that LSCmed prevalence remains low (5-10% of epithelial cells) when prostatic androgen receptor signaling unaltered (malignant Hi-Myc mice) but significantly increases in models exhibiting reduced prostatic androgen receptor signaling, rising up to 30% in premalignant tumors (Pb-PRL mice) and to >80% in castration-resistant prostate tumors driven by Pten loss (Ptenpc-/- mice). LSCmed tolerance to androgen deprivation was demonstrated by their persistence (Ptenpc-/-) or further enrichment (Pb-PRL) 2-3 weeks after castration as evidenced by FACS analysis. Transcriptomic analysis revealed that LSCmed represent a unique cell entity as their gene-expression profile is different from luminal and basal/stem cells, but shares markers of each. Their intrinsic androgen signaling is markedly decreased, which explains why LSCmed tolerate androgen-deprivation. This also enlightens why Ptenpc-/- tumors are castration-resistant since LSCmed represent the most prevalent cell type in this model. We validated CK4 as a specific marker for LSCmed on sorted cells and prostate tissues by immunostaining, allowing for the detection of LSCmed in various mouse prostate specimens. In castrated Ptenpc-/- prostates, BrdU staining revealed massive proliferation of CK4+ cells, further demonstrating their key role in castration-resistant prostate cancer progression. In all, this study identifies LSCmed as a probable source of prostate cancer relapse after androgen deprivation and as a new therapeutic target for the prevention of castrate-resistant prostate cancer.

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Expression data and H3K27me3 occupancy profiling by high throughput sequencing from control and SETD2 knockout organoids cells.

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