XAF1 promotes neuroblastoma tumor suppression and is required for KIF1Bβ-mediated apoptosis

Oncotarget. 2016 Jun 7;7(23):34229-39. doi: 10.18632/oncotarget.8748.

Abstract

Neuroblastoma is an aggressive, relapse-prone childhood tumor of the sympathetic nervous system. Current treatment modalities do not fully exploit the genetic basis between the different molecular subtypes and little is known about the targets discovered in recent mutational and genetic studies. Neuroblastomas with poor prognosis are often characterized by 1p36 deletion, containing the kinesin gene KIF1B. Its beta isoform, KIF1Bβ, is required for NGF withdrawal-dependent apoptosis, mediated by the induction of XIAP-associated Factor 1 (XAF1). Here, we showed that XAF1 low expression correlates with poor survival and disease status. KIF1Bβ deletion results in loss of XAF1 expression, suggesting that XAF1 is indeed a downstream target of KIF1Bβ. XAF1 silencing protects from NGF withdrawal and from KIF1Bβ-mediated apoptosis. Overexpression of XAF1 impairs tumor progression whereas knockdown of XAF1 promotes tumor growth, suggesting that XAF1 may be a candidate tumor suppressor in neuroblastoma and its associated pathway may be important for developing future interventions.

Keywords: KIF1Bβ; XAF1; apoptosis; neuroblastoma.

MeSH terms

  • Adaptor Proteins, Signal Transducing
  • Animals
  • Apoptosis / physiology
  • Apoptosis Regulatory Proteins
  • Biomarkers, Tumor / analysis
  • Cell Line, Tumor
  • F-Box Proteins / metabolism
  • Gene Expression Regulation, Neoplastic / physiology
  • Heterografts
  • Humans
  • Intracellular Signaling Peptides and Proteins / metabolism*
  • Kaplan-Meier Estimate
  • Kinesins / metabolism*
  • Mice
  • Mice, Knockout
  • Neoplasm Proteins / metabolism*
  • Neuroblastoma / metabolism
  • Neuroblastoma / mortality
  • Neuroblastoma / pathology*
  • Prognosis
  • Tumor Suppressor Proteins / metabolism

Substances

  • Adaptor Proteins, Signal Transducing
  • Apoptosis Regulatory Proteins
  • Biomarkers, Tumor
  • F-Box Proteins
  • Intracellular Signaling Peptides and Proteins
  • KIF1B protein, human
  • Kif1b protein, mouse
  • Neoplasm Proteins
  • Tumor Suppressor Proteins
  • XAF1 protein, human
  • XAF1 protein, mouse
  • Kinesins