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MYBL2 drives prostate cancer plasticity and identifies CDK2 as a therapeutic vulnerability in RB1-loss and neuroendocrine prostate cancer [ATAC-seq]

ABSTRACT: MYBL2 drives prostate cancer plasticity and identifies CDK2 as a therapeutic vulnerability in RB1-loss and neuroendocrine prostate cancer [ATAC-seq]

PROVIDER: PRJNA1130940 | ENA |

REPOSITORIES: ENA

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			Action	DRS
	SRR29684797_1.fastq.gz	Fastqsanger.gz
	SRR29684797_2.fastq.gz	Fastqsanger.gz
	SRR29684798_1.fastq.gz	Fastqsanger.gz
	SRR29684798_2.fastq.gz	Fastqsanger.gz
	SRR29684799_1.fastq.gz	Fastqsanger.gz

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MYBL2 drives prostate cancer plasticity and identifies CDK2 as a therapeutic vulnerability in RB1-loss and neuroendocrine prostate cancer

Project description:Phenotypic plasticity is a recognized mechanism driving therapeutic resistance in prostate cancer (PCa) patients. While underlying molecular causations driving phenotypic plasticity have been identified, therapeutic success is yet to be achieved. To identify putative master regulator transcription factors (MR-TF) driving phenotypic plasticity in PCa, this work utilized a multiomic approach using genetically engineered mouse models of prostate cancer combined with patient data to identify MYBL2 as a significantly enriched transcription factor in PCa exhibiting phenotypic plasticity. Genetic inhibition of Mybl2 using independent murine PCa cell lines representing phenotypic plasticity demonstrated Mybl2 loss significantly decreased in vivo growth as well as cell fitness and repressed gene expression signatures involved in pluripotency and stemness. Because MYBL2 is currently not druggable, a MYBL2 gene signature was employed to identify cyclin-dependent kinase-2 (CDK2) as a potential therapeutic target. CDK2 inhibition phenocopied genetic loss of Mybl2 and significantly decreased in vivo tumor growth associated with enrichment of DNA damage. Together, this work demonstrates MYBL2 as an important MR-TF driving phenotypic plasticity in PCa. Further, high MYBL2 activity identifies PCa that would be responsive to CDK2 inhibition.

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MYBL2 drives prostate cancer plasticity and identifies CDK2 as a therapeutic vulnerability in RB1-loss and neuroendocrine prostate cancer [ChIP-seq]

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MYBL2 drives prostate cancer plasticity and identifies CDK2 as a therapeutic vulnerability in RB1-loss and neuroendocrine prostate cancer [ATAC-seq]

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MYBL2 drives prostate cancer plasticity and identifies CDK2 as a therapeutic vulnerability in RB1-loss and neuroendocrine prostate cancer

Project description:MYBL2 drives prostate cancer plasticity and identifies CDK2 as a therapeutic vulnerability in RB1-loss and neuroendocrine prostate cancer

| PRJNA1131353 | ENA

MYBL2 drives prostate cancer plasticity and identifies CDK2 as a therapeutic vulnerability in RB1-loss and neuroendocrine prostate cancer [ChIP-seq]

Project description:MYBL2 drives prostate cancer plasticity and identifies CDK2 as a therapeutic vulnerability in RB1-loss and neuroendocrine prostate cancer [ChIP-seq]

| PRJNA1130939 | ENA

CDK2 knockdown in prostate cancer cell lines

Project description:CDK2 is a cyclin-dependent kinase involved in regulating cell cycle progression. In prostate cancer, CDK2 has been shown to be associated with poor survival. We sought to identify key genes and molecular pathways regulated by CDK2 in prostate cancer. We therefore knocked down CDK2 using siRNA in PC3 and ResA cell lines, and performed RNA-seq.

2025-07-16 | GSE282801 | GEO

CDK2 knockdown in prostate cancer cell lines

Project description:CDK2 knockdown in prostate cancer cell lines

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MYBL2 Drives Prostate Cancer Plasticity: Inhibiting Its Transcriptional Target CDK2 for RB1-Deficient Neuroendocrine Prostate Cancer.

Project description:Phenotypic plasticity is a recognized mechanism driving therapeutic resistance in patients with prostate cancer. Although underlying molecular causations driving phenotypic plasticity have been identified, therapeutic success is yet to be achieved. To identify putative master regulator transcription factors (MR-TF) driving phenotypic plasticity in prostate cancer, this work utilized a multiomic approach using genetically engineered mouse models of prostate cancer combined with patient data to identify MYB proto-oncogene like 2 (MYBL2) as a significantly enriched transcription factor in prostate cancer exhibiting phenotypic plasticity. Genetic inhibition of Mybl2 using independent murine prostate cancer cell lines representing phenotypic plasticity demonstrated Mybl2 loss significantly decreased in vivo growth as well as cell fitness and repressed gene expression signatures involved in pluripotency and stemness. Because MYBL2 is currently not druggable, a MYBL2 gene signature was employed to identify cyclin-dependent kinase-2 (CDK2) as a potential therapeutic target. CDK2 inhibition phenocopied genetic loss of Mybl2 and significantly decreased in vivo tumor growth associated with enrichment of DNA damage. Together, this work demonstrates MYBL2 as an important MR-TF driving phenotypic plasticity in prostate cancer. Furthermore, high MYBL2 activity identifies prostate cancer that would be responsive to CDK2 inhibition.SignificanceProstate cancers that escape therapy targeting the androgen receptor signaling pathways via phenotypic plasticity are currently untreatable. Our study identifies MYBL2 as a MR-TF in phenotypic plastic prostate cancer and implicates CDK2 inhibition as a novel therapeutic target for this most lethal subtype of prostate cancer.

| S-EPMC11368174 | biostudies-literature

CDK4/6 inhibits the STING signaling axis through RB1-dependent and RB1-independent pathways in prostate cancer

Project description:The efficacy of immunotherapy in prostate cancer is not satisfactory due to the “cold” tumor microenvironment and the paucity of neoantigens. The STING-TBK1-IRF3 signaling axis as core molecules of the innate immune system is increasingly recognized as a candidate target for cancer immunotherapy. Previou studies reported that CDK4/6 inhibitors induced DNA damage to activate the cGAS-STING pathway. However, the underlying mechanisms of how CDK4/6 inactivated the cGAS-STING pathway are still elusive. Here we revealed that treatment with CDK4/6 inhibitors enhance the anti-tumor effect of STING agonists in prostate cancer cells. Mechanically, CDK4/6 phosphorylated TBK1 at S527 to inactive the STING signaling pathway independent of RB1 in prostate cancer cell. Then, we also found that CDK4/6 phosphorylated RB1 at S249/T252 to induce the interaction of RB1 with TBK1 and diminish the phosphorylation of TBK1 at S172, which also suppresses the activation of the STING pathway. Collectively, we found that CDK4/6 inhibits the STING/TBK1/IRF3 axis through RB1-dependent and RB1-independent pathways in prostate cancer cells. These insights provide the novel evidence for CDK4/6 suppressing the innate immune response of prostate cancer.

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MYBL2/CREB1-Dependent Distinct FoxA1 Cistrome Directs G1/S Cell Cycle Progression in Androgen-Independent Prostate Cancer

Project description:FoxA1, in conjunction with MYBL2 and CREB1, governs G1/S cell-cycle transition in androgen-independent prostate cancer .

2011-12-08 | GSE26329 | GEO