Increased translation driven by non-canonical EZH2 creates a synthetic vulnerability in enzalutamide-resistant prostate cancer
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.
Authors
- Andrew Caleb Hsieh (ORCID: https://orcid.org/0000-0002-0897-1050)
- David W. Goodrich (ORCID: https://orcid.org/0000-0002-1021-1827)
- Jenna E. Moyer (ORCID: https://orcid.org/0000-0002-4599-2969)
- María T. Díaz‐Meco (ORCID: https://orcid.org/0000-0003-0147-0998)
- David S. Rickman (ORCID: https://orcid.org/0000-0001-7420-5883)
- Jorge Moscat (ORCID: https://orcid.org/0000-0002-9442-3834)
- Varadha Balaji Venkadakrishnan (ORCID: https://orcid.org/0000-0001-7071-4584)
- Juan Miguel Mosquera (ORCID: https://orcid.org/0000-0003-4666-6476)
- Himisha Beltran (ORCID: https://orcid.org/0000-0003-3259-2226)
- Antonio Marzio (ORCID: https://orcid.org/0000-0001-5959-012X)
- Mohd. Imran K. Khan (ORCID: https://orcid.org/0000-0001-5021-4814)
- Martin Bakht (ORCID: https://orcid.org/0000-0001-8803-2485)
- Brian D. Robinson (ORCID: https://orcid.org/0000-0001-5374-890X)
- Francesca Khani (ORCID: https://orcid.org/0000-0001-7238-8604)
- Olivier Elemento (ORCID: https://orcid.org/0000-0002-8061-9617)
- Marta Osrodek
- Miguel Reina‐Campos (ORCID: https://orcid.org/0000-0002-0704-4271)
- Shankha Subhra Chatterjee
- Nicholas J. Brady (ORCID: https://orcid.org/0000-0002-2928-0232)
- Tania Cid-Diaz
- Juan F. Linares
- Ángeles Durán (ORCID: https://orcid.org/0000-0001-9576-0587)
Institutions
- Roswell Park Comprehensive Cancer Center (US)
- La Jolla Institute for Immunology (US)
- Harvard University (US)
- University of Washington (US)
- Cornell University (US)
- Lander Institute (IL)
- Fred Hutch Cancer Center (US)
- Dana-Farber Cancer Institute (US)
- Weill Cornell Medicine (US)
Publication Details
- Journal
- Nature Communications
- Published
- 2024-11-20
- DOI
- https://doi.org/10.1038/s41467-024-53874-2
- Citations
- 10
- Primary Topic
- Prostate Cancer Treatment and Research
- Type
- article
- Field-Weighted Citation Impact
- 4.19
Funders
- Foundation for the National Institutes of Health
- Memorial Sloan-Kettering Cancer Center
- National Institutes of Health
- Weill Cornell Medical College
- National Cancer Institute