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RNA helicase A is a downstream mediator of KIF1Bβ tumor-suppressor function in neuroblastoma

Zhi Xiong Chen1, Karin Wallis, Stuart M Fell

  • 11Ludwig 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.

Cancer Discovery
|January 29, 2014
PubMed
Abstract

Insights

Kinesin KIF1B isoform β (KIF1Bβ) acts as a tumor suppressor by promoting apoptosis through nuclear DHX9 accumulation, which activates XAF1. Loss of KIF1Bβ in neuroblastoma impairs this pathway, potentially leading to tumor formation.

Area of Science:

  • Oncology
  • Molecular Biology
  • Developmental Biology

Background:

  • KIF1B mutations are linked to neuroblastomas and pheochromocytomas, suggesting KIF1B acts as a tumor suppressor, but its mechanism is unclear.
  • Neuroblastomas and pheochromocytomas originate from neural crest cells, which rely on growth factors like NGF during development.

Purpose of the Study:

  • To elucidate the tumor-suppressive mechanism of KIF1B, specifically KIF1B isoform β (KIF1Bβ).
  • To investigate the role of KIF1Bβ in apoptosis and its interaction with RNA helicase A (DHX9) in neural crest development and tumor pathogenesis.

Main Methods:

  • Investigated the interaction between KIF1Bβ and DHX9.
  • Assessed the impact of KIF1Bβ on DHX9 nuclear localization and XAF1 expression.
  • Examined the role of KIF1Bβ and DHX9 in NGF-dependent apoptosis during neural crest development.
  • Analyzed KIF1Bβ expression and DHX9 localization in neuroblastoma samples with 1p36 deletion.

Main Results:

  • KIF1Bβ interacts with DHX9, promoting its nuclear accumulation.
  • Nuclear DHX9 induces XIAP-associated factor 1 (XAF1) expression, leading to apoptosis.
  • KIF1Bβ is essential for developmental apoptosis triggered by nerve growth factor (NGF) competition.
  • NGF deprivation stimulates DHX9, which is required for apoptosis.
  • Neuroblastomas with 1p36 deletion show reduced KIF1Bβ and impaired DHX9 nuclear localization.

Conclusions:

  • KIF1Bβ functions as a neuroblastoma tumor suppressor by inducing apoptosis via nuclear DHX9 and XAF1 activation.
  • Loss of KIF1Bβ disrupts DHX9 localization, reduces NGF dependence in sympathetic neurons, and may contribute to tumor formation by impairing neural progenitor cell elimination.

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