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Supraphysiological Androgens Promote the Tumor Suppressive Activity of the Androgen Receptor Through cMYC Repression and Recruitment of the DREAM Complex

ABSTRACT: Supraphysiological Androgens Promote the Tumor Suppressive Activity of the Androgen Receptor Through cMYC Repression and Recruitment of the DREAM Complex

PROVIDER: PRJNA952101 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR23499601_1.fastq.gz	Fastqsanger.gz
	SRR23499601_2.fastq.gz	Fastqsanger.gz
	SRR23499602_1.fastq.gz	Fastqsanger.gz
	SRR23499602_2.fastq.gz	Fastqsanger.gz
	SRR23499603_1.fastq.gz	Fastqsanger.gz

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

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

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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]

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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]

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

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 outcomes in subsets of prostate cancer patients. However, the mechanism(s) contributing to SPA response 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 treat-ment whereas loss of DREAM complex components such as RBL1/2 promoted resistance. Over-expression of MYC resulted in complete resistance to SPA and attenuated the SPA/AR-mediated repression 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 stabil-ity are regulated by MYC, a key determinant of tumor sensitivity to SPA, treatment may hinge on effectively repressing MYC activity. The integrity of MYC signaling and DREAM complex assembly may consequently serve as determinants of SPA responses and as pathways mediating SPA resistance.

2023-05-26 | GSE225481 | GEO

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.

2023-05-26 | GSE228896 | GEO

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

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.

2023-05-26 | GSE228895 | GEO

Supraphysiological Androgens Promote the Tumor Suppressive Activity of the Androgen Receptor through cMYC Repression and Recruitment of the DREAM Complex.

Project description:The androgen receptor (AR) pathway regulates key cell survival programs in prostate epithelium. The AR represents a near-universal driver and therapeutic vulnerability in metastatic prostate cancer, and targeting AR has a remarkable therapeutic index. Though most approaches directed toward 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 outcomes in subsets of patients with prostate cancer. A better understanding of the mechanisms contributing to SPA response and resistance could help guide patient selection and combination therapies to improve efficacy. To characterize SPA signaling, we integrated metrics of gene expression changes induced by SPA together with cistrome data and protein-interactomes. These analyses indicated that the dimerization partner, RB-like, E2F, and multivulval 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. Overexpression of MYC resulted in complete resistance to SPA and attenuated the SPA/AR-mediated repression 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 complex. The integrity of MYC signaling and DREAM complex assembly may consequently serve as determinants of SPA responses and as pathways mediating SPA resistance.SignificanceDetermining the molecular pathways by which supraphysiological androgens promote growth arrest and treatment responses in prostate cancer provides opportunities for biomarker-selected clinical trials and the development of strategies to augment responses.

| S-EPMC10472100 | biostudies-literature

Supraphysiological Androgens Promote the Tumor Suppressive Activity of the Androgen Receptor Through cMYC Repression and Recruitment of the DREAM Complex

Project description:This SuperSeries is composed of the SubSeries listed below.

2023-05-26 | GSE228897 | GEO

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

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

| PRJNA489692 | ENA

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.

2019-07-09 | GSE119598 | GEO

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