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Supraphysiological Androgens Repress Prostate Cancer Growth and Induce DNA Damage Augmented by PARP Inhibition

ABSTRACT: Supraphysiological Androgens Repress Prostate Cancer Growth and Induce DNA Damage Augmented by PARP Inhibition

PROVIDER: PRJNA489692 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR7797420_1.fastq.gz	Fastqsanger.gz
	SRR7797420_2.fastq.gz	Fastqsanger.gz
	SRR7797421_1.fastq.gz	Fastqsanger.gz
	SRR7797421_2.fastq.gz	Fastqsanger.gz
	SRR7797422_1.fastq.gz	Fastqsanger.gz

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Supraphysiological Androgens Repress Prostate Cancer Growth and Induce DNA Damage Augmented by PARP Inhibition

Project description:Prostate cancer (PC) is initially dependent on androgen receptor (AR) signaling for survival and growth. Therapeutics designed to repress AR activity, such as those reducing circulating androgen levels, serve as the primary intervention for advanced disease. However, supraphysiological androgen (SPA) concentrations, can produce a paradoxical response leading to growth inhibition. We sought to determine the mechanisms by which SPA represses PC growth and determine if molecular context associates with anti-tumor effects.

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Depletion of PARP-2 in HepG2 cells

Project description:Poly(ADP-ribose) polymerase-2 (PARP-2) is acknowledged as a DNA repair enzyme; however, recently metabolic properties had been attributed to it. Hereby, we examined the metabolic consequences of PARP-2 ablation in liver. Microarray analysis of PARP-2 knockdown HepG2 cells revealed the dysregulation of lipid and cholesterol metabolism genes. Induction of cholesterol biosynthesis genes stemmed from the enhanced expression of sterol-regulatory element binding protein (SREBP)-1. We revealed that PARP-2 is a suppressor of the SREBP-1 promoter, therefore ablation of PARP-2 induces SREBP-1 expression and consequently cholesterol synthesis. PARP-2-/- mice had higher SREBP-1 expression that was translated into enhanced hepatic and serum cholesterol levels. PARP-2 silencing was performed employing shPARP-2 (small hairpin) and scPARP-2 (scrambled) shRNA by lentiviral delivery (Sigma) using 40 MOI lentiviruses coding shRNA sequence against PARP-2.

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Supraphysiological Androgens Promote the Tumor Suppressive Activity of the Androgen Receptor Through cMYC Repression and Recruitment of the DREAM Complex [CUT&RUN]

Project description:The androgen receptor (AR) pathway regulates key cell survival programs in prostate epithelium. Targeting the AR has a remarkable therapeutic index and represents a near-universal driver and therapeutic vulnerability in metastatic prostate cancer. Though most approaches directed toward the AR focus on inhibiting AR signaling, laboratory and now clinical data have shown that high dose, supraphysiological androgen treatment (SPA), results in growth repression and improved out-comes in subsets of prostate cancer patients. However, the mechanism(s) contributing to SPA re-sponse and resistance remain unclear. To characterize SPA signaling, we integrated metrics of gene expression changes induced by SPA together with cistrome data and protein-interactomes. These analyses determined that the Dimerization partner, RB-like, E2F and Multi-vulval class B (DREAM) complex mediates growth repression and downregulation of E2F targets in response to SPA. Notably, prostate cancers with complete genomic loss of RB1 responded to SPA treatment whereas loss of DREAM complex components such as RBL1/2 promoted resistance. Overexpres-sion of MYC resulted in complete resistance to SPA and attenuated the SPA/AR-mediated repres-sion of E2F target genes. These findings support a model of SPA-mediated growth repression that relies on the negative regulation of MYC by AR leading to repression of E2F1 signaling via the DREAM-SIN3A-HDAC complex. As RB1 and DREAM complex stability are regulated by MYC, a key determinant of tumor sensitivity to SPA, treatment may hinge on effectively repress-ing MYC activity. The integrity of MYC signaling and DREAM complex assembly may conse-quently serve as determinants of SPA responses and as pathways mediating SPA resistance.

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Supraphysiological Androgens Promote the Tumor Suppressive Activity of the Androgen Receptor Through cMYC Repression and Recruitment of the DREAM Complex [ChIP-seq]

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Immunogenicity of BRCA1-deficient Ovarian Cancers is Driven through DNA Sensing and is Augmented by PARP Inhibition (Hi-C)

Project description:Immunogenicity of BRCA1-deficient Ovarian Cancers is Driven through DNA Sensing and is Augmented by PARP Inhibition (Hi-C)

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Supraphysiological androgens suppress prostate cancer growth through androgen receptor-mediated DNA damage.

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PARP-1 regulation of alternative splicing

Project description:To address the global impact of PARP-1 on alternative splicing, we isolated total RNA in two biological replicates from control (non-treated), PARP-1 siRNA- and PJ-34-treated cells. Sequencing of these RNAs on an Illumina HiSeq 2500, yielded >56 million 100-bp paired-end RNA-seq reads. First we tested if PARP-1 KD was effective at the RNA-seq level. Read aligning to the entire gene body of PARP-1 shown a reduction in PARP-1 expression of about 1.5-fold (P-value < 0.0003), confirming that indeed PARP-1 was depleted after PARP-1 siRNA treatment. We next used these RNA-seq data sets (control, PARP-1 KD and PARylation inhibited) to assess whether these treatments resulted in changes in i) gene expression and ii) alternative splicing.

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