PARP1-mediated PARylation of TEAD4 stabilizes the YAP1-TEAD4 complex and promotes growth and immune evasion in breast cancer cells

The transcription coregulator YAP1 regulates numerous biological processes, including organ size control and tissue homeostasis. Consequently, abnormal YAP1 activation mediates various malignant characteristics, particularly in breast cancer Unfortunately, YAP1 is generally considered to be undruggable. Here, we found that PARP1 promotes the transcriptional activity of YAP1-TEAD4 complexes, breast cancer cell stemness, metastatic behavior, and evasion of antitumor immunity. This PARP1-mediated mechanism was independent of its role in the DNA damage response. Specifically, PARP1 directly interacted with the YAP1-TEAD4 complex and enhanced their interactions through PARP1-mediated PARylation of TEAD4 at a conserved Arg108Lys109 sequence. PARP1-enhanced YAP1-TEAD4 binding attenuated the interaction between YAP1 and the E3 ubiquitin ligase CRL4DCAF12, thus preventing its ubiquitylation and degradation. Furthermore, expression levels of PARP1 correlate with YAP1 and PD-L1 protein levels in breast cancer patient tissues and cells. Accordingly, simultaneous inhibition of PARP1 activity and blockade of PD-L1 enhanced CD8+/CD4+ cytolytic and tumor suppression functions in vivo. The findings reveal a PARP1-mediated regulatory mechanism for YAP1-TEAD4 transcriptional activity that may be targetable to suppress tumor growth and enhance immunotherapy.

转录共调节因子YAP1（transcription coregulator YAP1）调控众多生物学过程，包括器官大小调控与组织稳态。因此，YAP1的异常激活可介导多种恶性表型，在乳腺癌中尤为显著。然而，YAP1通常被认为是不可成药靶点。本研究发现，聚ADP核糖聚合酶1（PARP1）可增强YAP1-TEAD4复合物的转录活性、乳腺癌细胞干性、转移能力以及抗肿瘤免疫逃逸能力。该PARP1介导的调控机制不依赖于其在DNA损伤应答（DNA damage response）中的功能。具体而言，PARP1可直接结合YAP1-TEAD4复合物，并通过其介导的TEAD4在保守序列Arg108Lys109位点的聚ADP核糖基化修饰（PARylation）增强二者的结合。PARP1增强的YAP1-TEAD4结合会减弱YAP1与E3泛素连接酶CRL4DCAF12的相互作用，从而阻止YAP1的泛素化与降解。此外，在乳腺癌患者组织及细胞中，PARP1的表达水平与YAP1和PD-L1的蛋白水平呈显著相关。据此，同时抑制PARP1活性并阻断PD-L1，可在体内增强CD8+/CD4+T细胞的溶细胞活性与肿瘤抑制功能。本研究揭示了一种由PARP1介导的YAP1-TEAD4转录活性调控机制，该机制有望作为靶点用于抑制肿瘤生长并增强免疫治疗效果。