XAF1 promotes neuroblastoma tumor suppression and is required for KIF1Bβ-mediated apoptosis.
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.
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, S117597, Singapore, Singapore.
Zhang'e
Z
Choo
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, S117597, Singapore, Singapore.
Rachel Yu Lin
RY
Koh
Ludwig Cancer Research (Stockholm), Karolinska Institutet, SE-17177, Stockholm, Sweden.
Karin
K
Wallis
School of Life Sciences and Technology, Ngee Ann Polytechnic, S599489, Singapore, Singapore.
Timothy Jia Wei
TJ
Koh
Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, S299899, Singapore.
Chik Hong
CH
Kuick
Ludwig Cancer Research (Stockholm), Karolinska Institutet, SE-17177, Stockholm, Sweden.
Veronica
V
Sobrado
Neuro-Oncology Program, Moffitt Cancer Center, Tampa, FL 33612, USA.
Rajappa S
RS
Kenchappa
Department of Paediatric Surgery, KK Women's and Children's Hospital, S299899, Singapore, Singapore.
Amos Hong Pheng
AH
Loh
Department of Paediatric Hematology/Oncology, KK Women's and Children's Hospital, S299899, Singapore, Singapore.
Shui Yen
SY
Soh
Ludwig Cancer Research (Stockholm), Karolinska Institutet, SE-17177, Stockholm, Sweden.|Department of Microbiology and Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden.
Susanne
S
Schlisio
Department of Pathology and Laboratory Medicine, KK Women's and Children's Hospital, S299899, Singapore.
Kenneth Tou En
KT
Chang
Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, S117597, Singapore, Singapore.
Zhi Xiong
ZX
Chen
D048868:Adaptor Proteins, Signal Transducing; D000818:Animals; D017209:Apoptosis / Q000502:physiology; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor / Q000032:analysis; D045744:Cell Line, Tumor; D044783:F-Box Proteins / Q000378:metabolism; D015972:Gene Expression Regulation, Neoplastic / Q000502:physiology; D064593:Heterografts; D006801:Humans; D047908:Intracellular Signaling Peptides and Proteins / Q000378:metabolism*; D053208:Kaplan-Meier Estimate; D016547:Kinesins / Q000378:metabolism*; D051379:Mice; D018345:Mice, Knockout; D009363:Neoplasm Proteins / Q000378:metabolism*; D009447:Neuroblastoma / Q000378:metabolism / Q000401:mortality / Q000473:pathology*; D011379:Prognosis; D025521:Tumor Suppressor Proteins / Q000378:metabolism
D048868:Adaptor Proteins, Signal Transducing; D051017:Apoptosis Regulatory Proteins; D014408:Biomarkers, Tumor; D044783:F-Box Proteins; D047908:Intracellular Signaling Peptides and Proteins; C091053:KIF1B protein, human; C490398:Kif1b protein, mouse; D009363:Neoplasm Proteins; D025521:Tumor Suppressor Proteins; C417551:XAF1 protein, human; C528956:XAF1 protein, mouse; D016547:Kinesins
KIF1Bβ; XAF1; apoptosis; neuroblastoma