RNA helicase A is a downstream mediator of KIF1Bβ tumor-suppressor function in neuroblastoma.
Inherited KIF1B loss-of-function mutations in neuroblastomas and pheochromocytomas implicate the kinesin KIF1B as a 1p36.2 tumor suppressor. However, the mechanism of tumor suppression is unknown. We found that KIF1B isoform β (KIF1Bβ) interacts with RNA helicase A (DHX9), causing nuclear accumulation of DHX9, followed by subsequent induction of the proapoptotic 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.


CONCLUSIONS
KIF1Bβ has neuroblastoma tumor-suppressor properties and promotes and requires nuclear-localized DHX9 for its apoptotic function by activating XAF1 expression. Loss of KIF1Bβ alters subcellular localization of DHX9 and diminishes NGF dependence of sympathetic neurons, leading to reduced culling of neural progenitors, and, therefore, might predispose to tumor formation.
1Ludwig Institute for Cancer Research Ltd.; 2Department of Cell and Molecular Biology, Karolinska Institutet; 3Department of Women's and Children's Health, Karolinska University Hospital, Stockholm; 4Ludwig Institute for Cancer Research Ltd., Biomedical Center, Uppsala; 5Department of Clinical Genetics, Institute of Biomedicine, University of Gothenburg, Sahlgrenska University Hospital, Göteborg, Sweden; and 6Moffitt Cancer Center, Neuro-Oncology Program, Tampa, Florida.
Zhi Xiong
ZX
Chen
Karin
K
Wallis
Stuart M
SM
Fell
Veronica R
VR
Sobrado
Marie C
MC
Hemmer
Daniel
D
Ramsköld
Ulf
U
Hellman
Rickard
R
Sandberg
Rajappa S
RS
Kenchappa
Tommy
T
Martinson
John I
JI
Johnsen
Per
P
Kogner
Susanne
S
Schlisio
D000818:Animals; D017209:Apoptosis; D002467:Cell Nucleus / Q000378:metabolism; D002878:Chromosomes, Human, Pair 1; D053487:DEAD-box RNA Helicases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D028884:Karyopherins / Q000378:metabolism; D016547:Kinesins / Q000235:genetics / Q000378:metabolism*; D051379:Mice; D008810:Mice, Inbred C57BL; D009363:Neoplasm Proteins / Q000235:genetics / Q000378:metabolism*; D020932:Nerve Growth Factor / Q000235:genetics*; D009447:Neuroblastoma / Q000235:genetics*; D016716:PC12 Cells; D051381:Rats; D017384:Sequence Deletion; D013564:Sympathetic Nervous System / Q000378:metabolism; D014407:Tumor Cells, Cultured
D028884:Karyopherins; D009363:Neoplasm Proteins; D020932:Nerve Growth Factor; C098487:DHX9 protein, human; D053487:DEAD-box RNA Helicases; D016547:Kinesins