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| Status |
Public on Jul 30, 2024 |
| Title |
MYBL2 drives prostate cancer plasticity and identifies CDK2 as a therapeutic vulnerability in RB1-loss and neuroendocrine prostate cancer [ChIP-seq] |
| Organism |
Mus musculus |
| Experiment type |
Genome binding/occupancy profiling by high throughput sequencing
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| Summary |
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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| Overall design |
To investigate the change in the regulatory landscape in phenotypic plasticity in prostate cancer we performed H3K27ac ChIPseq in Pten KO (SKO) and Pten:Rb1 KO (DKO) GEMMs.
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| Contributor(s) |
Ellis L |
| Citation(s) |
39113611 |
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| Submission date |
Jul 02, 2024 |
| Last update date |
Sep 30, 2024 |
| Contact name |
Kun-Lin Ho |
| Organization name |
HJF
|
| Street address |
10322 Strathmore Hall St Apt 405
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| City |
Rockville |
| State/province |
MD |
| ZIP/Postal code |
20852 |
| Country |
USA |
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| Platforms (1) |
| GPL19057 |
Illumina NextSeq 500 (Mus musculus) |
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| Samples (3) |
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| Relations |
| BioProject |
PRJNA1130939 |
