Inherited KIF1Bβ loss-of-function mutations in neuroblastomas and pheochromocytomas implicate the kinesin KIF1Bβ as a 1p36.2 tumor suppressor. However, the mechanism of tumor suppression is unknown. We found that KIF1Bβ interacts with RNA helicase A (DHX9) causing nuclear accumulation of DHX9, followed by subsequent induction of the pro-apoptotic XIAP-associated Factor 1 (XAF1) and, consequently, apoptosis. Pheochromocytoma and neuroblastoma arise from neural crest progenitors that compete for growth factors such as nerve growth factor NGF during development. KIF1Bβ is required for developmental apoptosis induced by competition for NGF. We show that DHX9 is induced by and required for apoptosis stimulated by NGF deprivation. Moreover, neuroblastomas with chromosomal deletion of 1p36 exhibit loss of KIF1Bβ expression and impaired DHX9 nuclear localization, implicating the loss of DHX9 nuclear activity in neuroblastoma pathogenesis.
- Received July 11, 2013.
- Revision received January 7, 2014.
- Accepted January 22, 2014.
- Copyright © 2014, American Association for Cancer Research.