Increased translation driven by non-canonical EZH2 creates a synthetic vulnerability in enzalutamide-resistant prostate cancer
Abstract Overcoming resistance to therapy is a major challenge in castration-resistant prostate cancer (CRPC). Lineage plasticity towards a neuroendocrine phenotype enables CRPC to adapt and survive targeted therapies. However, the molecular mechanisms of epigenetic reprogramming during this process...
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| Format: | Article |
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Nature Portfolio
2024-11-01
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| Series: | Nature Communications |
| Online Access: | https://doi.org/10.1038/s41467-024-53874-2 |
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| author | Shankha S. Chatterjee Juan F. Linares Tania Cid-Diaz Angeles Duran Mohd. Imran K. Khan Marta Osrodek Nicholas J. Brady Miguel Reina-Campos Antonio Marzio Varadha Balaji Venkadakrishnan Martin K. Bakht Francesca Khani Juan Miguel Mosquera Brian D. Robinson Jenna Moyer Olivier Elemento Andrew C. Hsieh David W. Goodrich David S. Rickman Himisha Beltran Jorge Moscat Maria T. Diaz-Meco |
| author_facet | Shankha S. Chatterjee Juan F. Linares Tania Cid-Diaz Angeles Duran Mohd. Imran K. Khan Marta Osrodek Nicholas J. Brady Miguel Reina-Campos Antonio Marzio Varadha Balaji Venkadakrishnan Martin K. Bakht Francesca Khani Juan Miguel Mosquera Brian D. Robinson Jenna Moyer Olivier Elemento Andrew C. Hsieh David W. Goodrich David S. Rickman Himisha Beltran Jorge Moscat Maria T. Diaz-Meco |
| author_sort | Shankha S. Chatterjee |
| collection | DOAJ |
| description | Abstract Overcoming resistance to therapy is a major challenge in castration-resistant prostate cancer (CRPC). Lineage plasticity towards a neuroendocrine phenotype enables CRPC to adapt and survive targeted therapies. However, the molecular mechanisms of epigenetic reprogramming during this process are still poorly understood. Here we show that the protein kinase PKCλ/ι-mediated phosphorylation of enhancer of zeste homolog 2 (EZH2) regulates its proteasomal degradation and maintains EZH2 as part of the canonical polycomb repressive complex (PRC2). Loss of PKCλ/ι promotes a switch during enzalutamide treatment to a non-canonical EZH2 cistrome that triggers the transcriptional activation of the translational machinery to induce a transforming growth factor β (TGFβ) resistance program. The increased reliance on protein synthesis creates a synthetic vulnerability in PKCλ/ι-deficient CRPC. |
| format | Article |
| id | doaj-art-db3c11d3bad84c61a1e43ee2b9c64390 |
| institution | Kabale University |
| issn | 2041-1723 |
| language | English |
| publishDate | 2024-11-01 |
| publisher | Nature Portfolio |
| record_format | Article |
| series | Nature Communications |
| spelling | doaj-art-db3c11d3bad84c61a1e43ee2b9c643902024-11-24T12:33:23ZengNature PortfolioNature Communications2041-17232024-11-0115112310.1038/s41467-024-53874-2Increased translation driven by non-canonical EZH2 creates a synthetic vulnerability in enzalutamide-resistant prostate cancerShankha S. Chatterjee0Juan F. Linares1Tania Cid-Diaz2Angeles Duran3Mohd. Imran K. Khan4Marta Osrodek5Nicholas J. Brady6Miguel Reina-Campos7Antonio Marzio8Varadha Balaji Venkadakrishnan9Martin K. Bakht10Francesca Khani11Juan Miguel Mosquera12Brian D. Robinson13Jenna Moyer14Olivier Elemento15Andrew C. Hsieh16David W. Goodrich17David S. Rickman18Himisha Beltran19Jorge Moscat20Maria T. Diaz-Meco21Department of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineLa Jolla Institute for Immunology (LJI)Department of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineCaryl and Israel Englander Institute for Precision Medicine, Weill Cornell MedicineSandra and Edward Meyer Cancer Center, Weill Cornell MedicineDivision of Human Biology, Fred Hutchinson Cancer CenterPharmacology and Therapeutics, Roswell Park Comprehensive Cancer CenterDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Medical Oncology, Dana-Farber Cancer InstituteDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineDepartment of Pathology and Laboratory Medicine, Weill Cornell MedicineAbstract Overcoming resistance to therapy is a major challenge in castration-resistant prostate cancer (CRPC). Lineage plasticity towards a neuroendocrine phenotype enables CRPC to adapt and survive targeted therapies. However, the molecular mechanisms of epigenetic reprogramming during this process are still poorly understood. Here we show that the protein kinase PKCλ/ι-mediated phosphorylation of enhancer of zeste homolog 2 (EZH2) regulates its proteasomal degradation and maintains EZH2 as part of the canonical polycomb repressive complex (PRC2). Loss of PKCλ/ι promotes a switch during enzalutamide treatment to a non-canonical EZH2 cistrome that triggers the transcriptional activation of the translational machinery to induce a transforming growth factor β (TGFβ) resistance program. The increased reliance on protein synthesis creates a synthetic vulnerability in PKCλ/ι-deficient CRPC.https://doi.org/10.1038/s41467-024-53874-2 |
| spellingShingle | Shankha S. Chatterjee Juan F. Linares Tania Cid-Diaz Angeles Duran Mohd. Imran K. Khan Marta Osrodek Nicholas J. Brady Miguel Reina-Campos Antonio Marzio Varadha Balaji Venkadakrishnan Martin K. Bakht Francesca Khani Juan Miguel Mosquera Brian D. Robinson Jenna Moyer Olivier Elemento Andrew C. Hsieh David W. Goodrich David S. Rickman Himisha Beltran Jorge Moscat Maria T. Diaz-Meco Increased translation driven by non-canonical EZH2 creates a synthetic vulnerability in enzalutamide-resistant prostate cancer Nature Communications |
| title | Increased translation driven by non-canonical EZH2 creates a synthetic vulnerability in enzalutamide-resistant prostate cancer |
| title_full | Increased translation driven by non-canonical EZH2 creates a synthetic vulnerability in enzalutamide-resistant prostate cancer |
| title_fullStr | Increased translation driven by non-canonical EZH2 creates a synthetic vulnerability in enzalutamide-resistant prostate cancer |
| title_full_unstemmed | Increased translation driven by non-canonical EZH2 creates a synthetic vulnerability in enzalutamide-resistant prostate cancer |
| title_short | Increased translation driven by non-canonical EZH2 creates a synthetic vulnerability in enzalutamide-resistant prostate cancer |
| title_sort | increased translation driven by non canonical ezh2 creates a synthetic vulnerability in enzalutamide resistant prostate cancer |
| url | https://doi.org/10.1038/s41467-024-53874-2 |
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