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.