Despite some advances in controlling the progression of prostate cancer (PCa) that is refractory to the use of ADT/ARSI, most patients eventually succumb to the disease, and there is a pressing need to understand the mechanisms that lead to the development of CRPC. A common mechanism is the ability to integrate AR signals from vanishing levels of testosterone, with the frequent participation of YAP as a co-activator, and pointing to the deregulation of the Hippo pathway as a major determinant. We have recently shown that YAP is post-transcriptionally activated via the TLK1>NEK1 axis by stabilizing phosphorylation at Y407. We are now solidifying this work by showing the following: (1) The phosphorylation of Y407 is critical for YAP retention/partition in the nuclei, and J54 (TLK1i) reverses this along with YAP-Y407 dephosphorylation. (2) The enhanced degradation of (cytoplasmic) YAP is increased by J54 counteracting its Enzalutamide-induced accumulation. (3) The basis for all these effects, including YAP nuclear retention, can be explained by the stronger association of pYAP-Y407 with its transcriptional co-activators, AR and TEAD1. (4) We demonstrate that ChIP for GFP-YAP-wt, but hardly for the GFP-YAP-Y407F mutant, at the promoters of typical ARE- and TEAD1-driven genes is readily detected but becomes displaced after treatment with J54. (5) While xenografts of LNCaP cells show rapid regression following treatment with ARSI+J54, in the VCaP model, driven by theTMPRSS2-ERGoncogenic translocation, tumors initially respond well to the combination but subsequently recur, despite the continuous suppression of pNek1-T141 and pYAP-Y407. This suggests an alternative parallel pathway for CRPC progression for VCaP tumors in the long term, which may be separate from the observed ENZ-driven YAP deregulation, although clearly some YAP gene targets like PD-L1, that are found to accumulate following prolonged ENZ treatment, are still suppressed by the concomitant addition of J54.
尽管在控制对雄激素剥夺疗法/雄激素受体信号抑制剂耐药的去势抵抗性前列腺癌进展方面取得了一些进展，但大多数患者最终仍死于该疾病，因此迫切需要了解导致去势抵抗性前列腺癌发展的机制。一种常见机制是能够整合来自极低睾酮水平的雄激素受体信号，其中YAP作为共激活因子频繁参与，并指出Hippo通路失调是主要决定因素。我们最近发现，YAP通过TLK1>NEK1轴在Y407位点发生稳定磷酸化，从而在转录后被激活。目前我们通过以下发现进一步巩固了这项工作：（1）Y407的磷酸化对YAP在细胞核内的滞留/分布至关重要，而J54（TLK1抑制剂）能逆转这一过程并导致YAP-Y407去磷酸化。（2）J54通过抵消恩杂鲁胺诱导的YAP积累，增强了（胞质）YAP的降解。（3）所有这些效应（包括YAP核滞留）的基础，可以通过pYAP-Y407与其转录共激活因子（雄激素受体和TEAD1）更强的结合来解释。（4）我们证明，在典型的雄激素受体元件和TEAD1驱动基因的启动子区域，GFP-YAP野生型的染色质免疫沉淀信号容易检测到，而GFP-YAP-Y407F突变体几乎检测不到，但在J54处理后这些信号发生位移。（5）虽然LNCaP细胞异种移植瘤在雄激素受体信号抑制剂+J54治疗后迅速消退，但在由TMPRSS2-ERG致癌易位驱动的VCaP模型中，肿瘤最初对联合治疗反应良好，但随后复发，尽管pNek1-T141和pYAP-Y407持续受到抑制。这表明VCaP肿瘤的长期去势抵抗性前列腺癌进展可能存在另一条平行通路，可能与观察到的恩杂鲁胺驱动的YAP失调无关，尽管一些YAP基因靶点（如PD-L1）在长期恩杂鲁胺治疗后积累，但仍可通过同时添加J54来抑制。
肿瘤(癌症)患者之家