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.

克服对治疗的耐药性是去势抵抗性前列腺癌 （CRPC） 的一项重大挑战。对神经内分泌表型的谱系可塑性使 CRPC 能够适应靶向治疗并在靶向治疗中存活。然而，在此过程中表观遗传重编程的分子机制仍然知之甚少。在这里，我们表明蛋白激酶 PKCλ/ι 介导的 zeste 同源物增强子 2 （EZH2） 磷酸化调节其蛋白酶体降解并维持 EZH2 作为经典多梳抑制复合物 （PRC2） 的一部分。PKCλ/ι 的缺失促进了恩杂鲁胺治疗期间向非经典 EZH2 cistrome 的转变，从而触发翻译机制的转录激活，以诱导转化生长因子 β （TGFβ） 耐药程序。对蛋白质合成的依赖增加在 PKCλ/ι 缺陷型 CRPC 中产生了合成脆弱性。