The VEGF receptor neuropilin 2 promotes homologous recombination by stimulating YAP/TAZ-mediated Rad51 expression

Abstract

Vascular endothelial growth factor (VEGF) signaling in tumor cells mediated by neuropilins (NRPs) contributes to the aggressive nature of several cancers, including triple-negative breast cancer (TNBC), independently of its role in angiogenesis. Understanding the mechanisms by which VEGF–NRP signaling contributes to the phenotype of such cancers is a significant and timely problem. We report that VEGF–NRP2 promote homologous recombination (HR) in BRCA1 wild-type TNBC cells by contributing to the expression and function of Rad51, an essential enzyme in the HR pathway that mediates efficient DNA double-strand break repair. Mechanistically, we provide evidence that VEGF–NRP2 stimulates YAP/TAZ-dependent Rad51 expression and that Rad51 is a direct YAP/TAZ–TEAD transcriptional target. We also discovered that VEGF–NRP2–YAP/TAZ signaling contributes to the resistance of TNBC cells to cisplatin and that Rad51 rescues the defects in DNA repair upon inhibition of either VEGF–NRP2 or YAP/TAZ. These findings reveal roles for VEGF–NRP2 and YAP/TAZ in DNA repair, and they indicate a unified mechanism involving VEGF–NRP2, YAP/TAZ, and Rad51 that contributes to resistance to platinum chemotherapy.

CDK5 Activates Hippo Signaling to Confer Resistance to Radiation Therapy Via Upregulating TAZ in Lung Cancer

“…21 Moreover, TAZ was found to contribute to Rad51 expression and promote homologous recombination in breast cancer. 22 Collectively, these studies strongly support the idea that Hippo signaling pathway activation is closely associated with oncogenesis and cancer radioresistance.…”

Endothelial cell HSPA12B and yes-associated protein cooperatively regulate angiogenesis following myocardial infarction

“…Because we observed that YAP inhibition decreased HSPA12B mRNA levels ( Figure 4G ), we next investigated whether HSPA12B was a direct transcriptional target of YAP in HUVECs. YAP controls gene transcription via binding to TEAD around the promoter or enhancer of target genes ( 36 , 37 ). Therefore, we searched for and identified TEAD4-binding motif in the HSPA12B gene-enhancer regions.…”

RETRACTED: OTUB2 Promotes Homologous Recombination Repair Through Stimulating Rad51 Expression in Endometrial Cancer

“…Moreover, YAP and TAZ function as oncogenes via translocation into nucleus during cancer metastasis 36 . OTUB2 deubiquitinates YAP/TAZ for cancer metastasis 37 , and YAP/TAZ-mediated Rad51 expression facilitates for HR during resistance to platinum chemotherapy 38 . Therefore, YAP/TAZ signaling pathway might be involved in OTUB2-mediated HR in endometrial cancer.…”