KIF1Bβ Functions as a Haploinsufficient Tumor Suppressor Gene Mapped to Chromosome 1p36.2 by Inducing Apoptotic Cell Death

Abstract

Deletion of the distal region of chromosome 1 frequently occurs in a variety of human cancers, including aggressive neuroblastoma. Previously, we have identified a 500-kb homozygously deleted region at chromosome 1p36.2 harboring at least six genes in a neuroblastoma-derived cell line NB1/C201. Among them, only KIF1Bbeta, a member of the kinesin superfamily proteins, induced apoptotic cell death. These results prompted us to address whether KIF1Bbeta could be a tumor suppressor gene mapped to chromosome 1p36 in neuroblastoma. Hemizygous deletion of KIF1Bbeta in primary neuroblastomas was significantly correlated with advanced stages (p = 0.0013) and MYCN amplification (p < 0.001), whereas the mutation rate of the KIF1Bbeta gene was infrequent. Although KIF1Bbeta allelic loss was significantly associated with a decrease in KIF1Bbeta mRNA levels, its promoter region was not hypermethylated. Additionally, expression of KIF1Bbeta was markedly down-regulated in advanced stages of tumors (p < 0.001). Enforced expression of KIF1Bbeta resulted in an induction of apoptotic cell death in association with an increase in the number of cells entered into the G2/M phase of the cell cycle, whereas its knockdown by either short interfering RNA or by a genetic suppressor element led to an accelerated cell proliferation or enhanced tumor formation in nude mice, respectively. Furthermore, we demonstrated that the rod region unique to KIF1Bbeta is critical for the induction of apoptotic cell death in a p53-independent manner. Thus, KIF1Bbeta may act as a haploinsufficient tumor suppressor, and its allelic loss may be involved in the pathogenesis of neuroblastoma and other cancers.