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

Autor:	Elaimy AL; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605.; Medical Scientist Training Program, University of Massachusetts Medical School, Worcester, MA 01605., Amante JJ; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605., Zhu LJ; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605.; Department of Molecular Medicine, University of Massachusetts Medical School, Worcester, MA 01605.; Department of Bioinformatics and Integrative Biology, University of Massachusetts Medical School, Worcester, MA 01605., Wang M; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605., Walmsley CS; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605., FitzGerald TJ; Department of Radiation Oncology, University of Massachusetts Medical School, Worcester, MA 01605., Goel HL; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605., Mercurio AM; Department of Molecular, Cell and Cancer Biology, University of Massachusetts Medical School, Worcester, MA 01605; arthur.mercurio@umassmed.edu.
Jazyk:	angličtina
Zdroj:	Proceedings of the National Academy of Sciences of the United States of America [Proc Natl Acad Sci U S A] 2019 Jul 09; Vol. 116 (28), pp. 14174-14180. Date of Electronic Publication: 2019 Jun 24.
DOI:	10.1073/pnas.1821194116
Abstrakt:	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. Competing Interests: The authors declare no conflict of interest.
Databáze:	MEDLINE
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