TY - JOUR TI - YAP-mediated repression of HRK regulates tumor growth, therapy response, and survival under tumor environmental stress in neuroblastoma AU - Shim, Jenny AU - Lee, Jasmine Y. AU - Jonus, Hunter C. AU - Arnold, Amanda AU - Schnepp, Robert W. AU - Janssen, Kaitlyn M. AU - Maximov, Victor AU - Goldsmith, Kelly C. T2 - Cancer Research AB - Following chemotherapy and relapse, high-risk neuroblastoma tumors harbor more genomic alterations than at diagnosis, including increased transcriptional activity of the Yes-Associated Protein (YAP), a key downstream component of the Hippo signaling network. Although YAP has been implicated in many cancer types, its functional role in the aggressive pediatric cancer neuroblastoma (NB) is not well characterized. In this study, we performed genetic manipulation of YAP in human-derived NB cell lines to investigate YAP function in key aspects of the malignant phenotype, including mesenchymal properties, tumor growth, chemotherapy response, and MEK inhibitor response. Standard cytotoxic therapy induced YAP expression and transcriptional activity in patient-derived xenografts treated in vivo, which may contribute to neuroblastoma recurrence. Moreover, YAP promoted a mesenchymal phenotype in high-risk neuroblastoma that modulated tumor growth and therapy resistance in vivo. Finally, the BH3-only protein Harakiri (HRK) was identified as a novel target inhibited by YAP which, when suppressed, prevented apoptosis in response to nutrient deprivation in vitro and promoted tumor aggression, chemotherapy resistance, and MEK inhibitor resistance in vivo. Collectively, these findings suggest that YAP inhibition may improve chemotherapy response in neuroblastoma patients via its regulation of HRK, thus providing a critical strategic complement to MEK inhibitor therapy. DA - 2020/01/01/ PY - 2020 DO - 10.1158/0008-5472.CAN-20-0025 DP - cancerres.aacrjournals.org J2 - Cancer Res LA - en SN - 0008-5472, 1538-7445 UR - https://cancerres.aacrjournals.org/content/early/2020/09/05/0008-5472.CAN-20-0025 Y2 - 2020/09/09/18:51:00 ER -