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

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): Homo sapiens

PROVIDER: GSE266954 | 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)

Project description: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.

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Project description:Identification of phosphopeptides EZH2 in control and kinase-deficient cells. The HA-EZH2 plasmid was transfected in HEK 293T cells, and HA-EZH2 was subsequently purified using HA peptide. The elution was performed with 1mg/mL HA-peptide in Tris buffered saline (TBS with 150mM NaCl), pH 7.5 in a final volume of 100 microL and a concentration of 150-250 ng/microL. Two samples were sent to the facility for analysis: HEK293T-sgC and sgPRKCI.

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