Project description:Genomic loss of RB1 is a common alteration in castration-resistant prostate cancer (CRPC) and is associated with poor patient outcomes. RB1-loss is also a driver event that promotes the neuroendocrine transdifferentiation of prostate cancer (PCa). The loss of Rb protein disrupts the Rb-E2F repressor complex and thus hyperactivates E2F transcription activators. While the impact of RB1-loss on PCa progression and linage plasticity has been previously studied, the underline mechanisms remain unclear. Using an integrated cistromic and transcriptomic analysis, we have characterized Rb activities in multiple CRPC models by identifying Rb directly regulated genes and revealed that Rb has distinct binding sites and targets in TP53-mutated CRPC. Significantly, we show that RB1-loss promotes the noncanonical activator function of LSD1/KDM1A, which stabilizes chromatin binding of E2F1, and hence sensitizes CRPC tumor to the LSD1 inhibitor treatment. These results provide new molecular insights of Rb activity in PCa progression and suggest LSD1 as a potential therapeutic target in CRPC with RB1-loss.
Project description:Genomic loss of RB1 is a common alteration in castration-resistant prostate cancer (CRPC) and is associated with poor patient outcomes. RB1-loss is also a driver event that promotes the neuroendocrine transdifferentiation of prostate cancer (PCa). The loss of Rb protein disrupts the Rb-E2F repressor complex and thus hyperactivates E2F transcription activators. While the impact of RB1-loss on PCa progression and linage plasticity has been previously studied, the underline mechanisms remain unclear. Using an integrated cistromic and transcriptomic analysis, we have characterized Rb activities in multiple CRPC models by identifying Rb directly regulated genes and revealed that Rb has distinct binding sites and targets in TP53-mutated CRPC. Significantly, we show that RB1-loss promotes the noncanonical activator function of LSD1/KDM1A, which stabilizes chromatin binding of E2F1, and hence sensitizes CRPC tumor to the LSD1 inhibitor treatment. These results provide new molecular insights of Rb activity in PCa progression and suggest LSD1 as a potential therapeutic target in CRPC with RB1-loss.
Project description:Castration-resistant prostate cancer (CRPC) is refractory to hormone treatment, and its progression mechanism is not fully uncovered. This study aims to clarify the role and mechanism of Human antigen R (HuR) as a therapeutic target for CRPC progression.
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.
Project description:Prostate cancer is one of the major cancers that seriously affect men's health. It has high morbidity and high mortality, but there is still no ideal molecular markers for the diagnosis and prognosis of prostate cancer. Castration-resistant prostate cancer is associated with wide variations in survival. To determine whether differentially expressed circRNAs in plasma exosomes can be used as a novel biomarker for castration-resistant prostate cancer prognosis, we performed high-throughput circRNA sequencing on 15 pairs of plasma exosomes from 30 metastatic castration-resistant prostate cancer patients, with or without early progression, to screen differentially expressed circRNAs.
Project description:RB1 loss promotes a noncanonical activator function of LSD1 and sensitizes castration-resistant prostate cancer to LSD1 inhibition [ChIP-seq]