Radiation-induced YAP/TEAD4 binding confers non-small cell lung cancer radioresistance via promoting NRP1 transcription

Abstract Despite the importance of radiation therapy as a non-surgical treatment for non-small cell lung cancer (NSCLC), radiation resistance has always been a concern, due to poor patient response and prognosis. Therefore, it is crucial to uncover novel targets to enhance radiotherapy and investigate the mechanisms underlying radiation resistance. Previously, we demonstrated that NRP1 was connected to radiation resistance in NSCLC cells. In the present study, bioinformatics analysis of constructed radiation-resistant A549 and H1299 cell models revealed that transcription coactivator YAP is a significant factor in cell proliferation and metastasis. However, there has been no evidence linking YAP and NRP1 to date. In this research, we have observed that YAP contributes to radiation resistance in NSCLC cells by stimulating cell proliferation, migration, and invasion. Mechanistically, YAP dephosphorylation after NSCLC cell radiation. YAP acts as a transcription co-activator by binding to the transcription factor TEAD4, facilitating TEAD4 to bind to the NRP1 promoter region and thereby increasing NRP1 expression. NRP1 has been identified as a new target gene for YAP/TEAD4. Notably, when inhibiting YAP binds to TEAD4, it inhibits NRP1 expression, and Rescue experiments show that YAP/TEAD4 influences NRP1 to regulate cell proliferation, metastasis and leading to radiation resistance generation. According to these results, YAP/TEAD4/NRP1 is a significant mechanism for radioresistance and can be utilized as a target for enhancing radiotherapy efficacy.