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

Area of Science:

• Oncology
• Molecular Biology
• Epigenetics

Background:

• Therapy resistance in castration-resistant prostate cancer (CRPC) is a significant clinical challenge.
• Lineage plasticity, particularly towards a neuroendocrine phenotype, allows CRPC cells to survive therapies.
• The epigenetic mechanisms driving this adaptive resistance remain largely unknown.

Purpose of the Study:

• To investigate the role of protein kinase lambda/iota (PKCλ/ι) in regulating enhancer of zeste homolog 2 (EZH2) and its impact on CRPC therapy resistance.
• To elucidate the molecular mechanisms of epigenetic reprogramming that facilitate CRPC adaptation to targeted therapies.

Main Methods:

• Investigated the phosphorylation of EZH2 by PKCλ/ι and its effect on EZH2 proteasomal degradation.
• Analyzed the EZH2 cistrome switch under enzalutamide treatment in PKCλ/ι-deficient CRPC models.
• Assessed the transcriptional activation of the translational machinery and the induction of transforming growth factor beta (TGFβ) resistance programs.

Main Results:

• PKCλ/ι-mediated phosphorylation of EZH2 is crucial for its proteasomal degradation and its canonical role within the Polycomb Repressive Complex 2 (PRC2).
• Loss of PKCλ/ι during enzalutamide treatment leads to a shift in EZH2 binding (cistrome) to non-canonical sites.
• This aberrant EZH2 localization triggers increased protein synthesis and activates a TGFβ-mediated resistance program.

Conclusions:

• PKCλ/ι plays a critical role in maintaining EZH2 function and preventing adaptive resistance in CRPC.
• Disruption of PKCλ/ι function promotes a lineage plasticity-driven resistance mechanism involving EZH2 and TGFβ signaling.
• PKCλ/ι-deficient CRPC exhibits increased reliance on protein synthesis, presenting a potential synthetic vulnerability for therapeutic targeting.