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

// Zhang’e Choo 1 , Rachel Yu Lin Koh 1 , Karin Wallis 2 , Timothy Jia Wei Koh 3 , Chik Hong Kuick 4 , Veronica Sobrado 2 , Rajappa S. Kenchappa 5 , Amos Hong Pheng Loh 6 , Shui Yen Soh 7 , Susanne Schlisio 2, 8 , Kenneth Tou En Chang 4 , Zhi Xiong Chen 1 1 Department of Physiology, Yong Loo Lin School of Medicine, National University of Singapore, S117597, Singapore, Singapore 2 Ludwig Cancer Research (Stockholm), Karolinska Institutet, SE-17177, Stockholm, Sweden 3 School of Life Sciences and Technology, Ngee Ann Polytechnic, S599489, Singapore, Singapore 4 Department of Pathology and Laboratory Medicine, KK Women’s and Children’s Hospital, S299899, Singapore 5 Neuro-Oncology Program, Moffitt Cancer Center, Tampa, FL 33612, USA 6 Department of Paediatric Surgery, KK Women’s and Children’s Hospital, S299899, Singapore, Singapore 7 Department of Paediatric Hematology/Oncology, KK Women’s and Children’s Hospital, S299899, Singapore, Singapore 8 Department of Microbiology and Tumor and Cell Biology, Karolinska Institutet, 17177 Stockholm, Sweden Correspondence to: Zhi Xiong Chen, email: zhixiong_chen@nuhs.edu.sg Keywords: XAF1, neuroblastoma, KIF1Bβ, apoptosis Received: August 13, 2015     Accepted: March 28, 2016     Published: April 15, 2016 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.