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

ABSTRACT: YAP1 is participated in numerous biological processes including organ size control and tissue homeostasis. We previously reported that abnormal YAP1 activation accounted for the malignant characteristics of breast cancer, including stemness, metastasis and drug resistance. However, as a transcription coregulator, YAP1 was generally considered to be an undruggable target, which limits its further clinical application. Here, using co-immunoprecipitation and mass spectrometry analysis, we identified PARP1 as a novel regulator in the control of YAP1-TEAD4 transcriptional activity, breast cancer cell stemness, metastasis and immune evasion, which was independent on DNA damage response. Specifically, we found PARP1 directly interacted with YAP1-TEAD4 complex and enhanced their interactions through PARP1-mediated TEAD4 PARylation at a novel conserved R108K109 site. Moreover, PARP1-mediated YAP1-TEAD4 binding attenuated YAP1 interaction with CRL4DCAF12, and thus prevented YAP1 ubiquitination and degradation in cell nucleus. In addition, 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. Overall, our findings not only reveal a new regulatory mechanism for PARP1-mediated YAP1-TEAD4 transcriptional activity, but also provide translational implications of targeting PARP1 for YAP1-TEAD4 complex-based anti-tumor therapy.

ORGANISM(S): Homo Sapiens

SUBMITTER: Peng Li

PROVIDER: PXD068941 | iProX | Fri Sep 26 00:00:00 BST 2025

REPOSITORIES: iProX

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