Increased translation driven by non-canonical EZH2 creates a synthetic vulnerability in enzalutamide-resistant prostate cancer

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 () and Maria T. Diaz-Meco ()
Additional contact information
Shankha S. Chatterjee: Weill Cornell Medicine
Juan F. Linares: Weill Cornell Medicine
Tania Cid-Diaz: Weill Cornell Medicine
Angeles Duran: Weill Cornell Medicine
Mohd. Imran K. Khan: Weill Cornell Medicine
Marta Osrodek: Weill Cornell Medicine
Nicholas J. Brady: Weill Cornell Medicine
Miguel Reina-Campos: La Jolla Institute for Immunology (LJI)
Antonio Marzio: Weill Cornell Medicine
Varadha Balaji Venkadakrishnan: Dana-Farber Cancer Institute
Martin K. Bakht: Dana-Farber Cancer Institute
Francesca Khani: Weill Cornell Medicine
Juan Miguel Mosquera: Weill Cornell Medicine
Brian D. Robinson: Weill Cornell Medicine
Jenna Moyer: Weill Cornell Medicine
Olivier Elemento: Weill Cornell Medicine
Andrew C. Hsieh: Fred Hutchinson Cancer Center
David W. Goodrich: Roswell Park Comprehensive Cancer Center
David S. Rickman: Weill Cornell Medicine
Himisha Beltran: Dana-Farber Cancer Institute
Jorge Moscat: Weill Cornell Medicine
Maria T. Diaz-Meco: Weill Cornell Medicine

Nature Communications, 2024, vol. 15, issue 1, 1-23

Abstract: 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.

Date: 2024
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DOI: 10.1038/s41467-024-53874-2

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