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

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. RNA-seq of LNCaP sgPRKCI and sgC treated with Enzalutamide

治疗抵抗是去势抵抗性前列腺癌（castration-resistant prostate cancer, CRPC）面临的主要难题。向神经内分泌表型的谱系可塑性使得CRPC能够适应靶向治疗并存活，但该过程中表观遗传重编程的分子机制仍不甚明确。本研究发现，蛋白激酶PKCl/i可磷酸化表观遗传调控因子zeste同源增强子2（enhancer of zeste homologue 2, EZH2），调控其蛋白酶体降解，并维持EZH2作为经典多梳抑制复合体2（canonical polycomb repressive complex 2, PRC2）的组成部分发挥功能。PKCl/i的缺失会促使恩扎卢胺治疗过程中细胞转向非经典EZH2顺式调控组，进而触发翻译机器相关基因的转录激活，诱导转化生长因子β（transforming growth factor β, TGFβ）抵抗程序。对蛋白质合成依赖程度的增强会在PKCl/i缺陷型CRPC中形成合成易感脆弱性。本研究对经恩扎卢胺处理的LNCaP-sgPRKCI与LNCaP-sgC细胞进行了RNA测序（RNA-seq）