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

Nat Commun. 2024 Nov 20;15(1):9755. doi: 10.1038/s41467-024-53874-2.

Shankha S Chatterjee ^# ¹ ², Juan F Linares ^# ¹ ², Tania Cid-Diaz ^# ¹ ², Angeles Duran ^# ¹ ², Mohd Imran K Khan ¹ ², Marta Osrodek ¹ ², Nicholas J Brady ¹ ², Miguel Reina-Campos ³, Antonio Marzio ¹ ², Varadha Balaji Venkadakrishnan ⁴ ⁵, Martin K Bakht ⁴ ⁵, Francesca Khani ¹, Juan Miguel Mosquera ¹ ⁶, Brian D Robinson ¹, Jenna Moyer ⁶, Olivier Elemento ² ⁶, Andrew C Hsieh ⁷ ⁸ ⁹, David W Goodrich ¹⁰, David S Rickman ¹ ², Himisha Beltran ⁴ ⁵, Jorge Moscat ¹¹ ¹², Maria T Diaz-Meco ¹³ ¹⁴

Affiliations

1 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA.
2 Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA.
3 La Jolla Institute for Immunology (LJI), La Jolla, CA, USA.
4 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, MA, USA.
5 Harvard Medical School, Boston, MA, USA.
6 Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine, New York, NY, USA.
7 Division of Human Biology, Fred Hutchinson Cancer Center, Seattle, WA, USA.
8 Department of Genomic Sciences, University of Washington, Seattle, WA, USA.
9 Department of Medicine, University of Washington, Seattle, WA, USA.
10 Pharmacology and Therapeutics, Roswell Park Comprehensive Cancer Center, Buffalo, NY, USA.
11 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. jom4010@med.cornell.edu.
12 Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. jom4010@med.cornell.edu.
13 Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, New York, NY, USA. mtd4001@med.cornell.edu.
14 Sandra and Edward Meyer Cancer Center, Weill Cornell Medicine, New York, NY, USA. mtd4001@med.cornell.edu.
# Contributed equally.

PMID: 39567499 DOI: 10.1038/s41467-024-53874-2

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.

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HY-14944

Homoharringtonine

99.96%, STAT Inhibitor

STAT

Cancer

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