XAF1 promotes neuroblastoma tumor suppression and is required for KIF1Bβ-mediated apoptosis
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Zhang’e Choo1, Rachel Yu Lin Koh1, Karin Wallis2, Timothy Jia Wei Koh3, Chik Hong Kuick4, Veronica Sobrado2, Rajappa S. Kenchappa5, Amos Hong Pheng Loh6, Shui Yen Soh7, Susanne Schlisio2,8, Kenneth Tou En Chang4, Zhi Xiong Chen1
1Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, S117597, Singapore, Singapore
2Ludwig Cancer Research (Stockholm), Karolinska Institutet, SE-17177, Stockholm, Sweden
3School of Life Sciences and Technology, Ngee Ann Polytechnic, S599489, Singapore, Singapore
4Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, S299899, Singapore
5Neuro-Oncology Program, Moffitt Cancer Center, Tampa, FL 33612, USA
6Department of Paediatric Surgery, KK Women’s and Children’s Hospital, S299899, Singapore, Singapore
7Department of Paediatric Hematology/Oncology, KK Women’s and Children’s Hospital, S299899, Singapore, Singapore
8Department of Microbiology and Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden
Zhi Xiong Chen, email: [email protected]
Keywords: XAF1, neuroblastoma, KIF1Bβ, apoptosis
Received: August 13, 2015 Accepted: March 28, 2016 Published: April 15, 2016
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.
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