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Increased translation driven by a non-canonical EZH2 cistrome creates a synthetic vulnerability in enzalutamide-resistant prostate cancer (scRNA-Seq)

ABSTRACT: 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 PKCl/i phosphorylates the epigenetic regulator enhancer of zeste homologue 2 (EZH2) to regulate its proteasomal degradation and maintain EZH2 as part of the canonical polycomb repressive complex (PRC2). Loss of PKCl/i 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 b (TGFb) resistance program. The increased reliance on protein synthesis creates a synthetic vulnerability in PKCl/i-deficient CRPC.

ORGANISM(S): Mus musculus

PROVIDER: GSE266955 | GEO | 2024/10/22

REPOSITORIES: GEO

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Increased translation driven by a non-canonical EZH2 cistrome creates a synthetic vulnerability in enzalutamide-resistant prostate cancer (CUT&RUN)

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