RNA Helicase A Is a Downstream Mediator of KIF1Bβ Tumor-Suppressor Function in Neuroblastoma

Abstract

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. SIGNIFICANCE: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. Cancer Discov; 4(4); 434-51.

Rare Germline Mutations Identified by Targeted Next-Generation Sequencing of Susceptibility Genes in Pheochromocytoma and Paraganglioma

“…Here we report a pheochromocytoma patient with a germline missense mutation in KIF1B␤ who later presented with an endometrial carcinoma. The mutation affects a highly conserved region of the protein close to the site of the functionally relevant T827I mutation identified in neuroblastoma (8,28). Another PCC had a somatic missense mutation in KIF1B␤ in combination with a germline NF1 mutation.…”

DHX33 Transcriptionally Controls Genes Involved in the Cell Cycle

“…Many characterized RNA helicases have been found to be fundamental in essential cellular processes (1,26). In recent years, a few RNA helicases have been found to participate in cancer development even though their detailed molecular mechanisms remain largely undiscovered (27)(28)(29)(30)(31)(32)(33). Furthermore, despite the characterization of several DEAD/DEAH proteins, few specific inhibitors targeting these ATP-dependent helicases have been developed.…”

Genetic Alterations in Pheochromocytoma and Paraganglioma

“…The mutation was predicted as pathogenic and affects a highly conserved region of the protein close to the site of a mutation previously identified in neuroblastoma 72 , which has been shown to be of functional importance 238 . Even though it was only detected in one case, the frequency in apparently sporadic pheochromocytomas (1.7%) is similar to the previously reported frequencies of germline MAX and TMEM127 mutations 67,76 .…”