KIF1Bβ functions as a haploinsufficient tumor suppressor gene mapped to chromosome 1p36.2 by inducing apoptotic cell death

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 KIF1B beta, a member of the kinesin superfamily proteins, induced apoptotic cell death. These results prompted us to address whether KIF1B beta could be a tumor suppressor gene mapped to chromosome 1p36 in neuroblastoma. Hemizygous deletion of KIF1B beta in primary neuroblastomas was significantly correlated with advanced stages (p = 0.0013) and MYCN amplification (p < 0.001), whereas the mutation rate of the KIF1B beta gene was infrequent. Although KIF1B beta allelic loss was significantly associated with a decrease in KIF1B beta mRNA levels, its promoter region was not hypermethylated. Additionally, expression of KIF1B beta was markedly down-regulated in advanced stages of tumors (p < 0.001). Enforced expression of KIF1B beta resulted in an induction of apoptotic cell death in association with an increase in the number of cells entered into the G(2)/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 KIF1B beta is critical for the induction of apoptotic cell death in a p53-independent manner. Thus, KIF1B beta may act as a haploinsufficient tumor suppressor, and its allelic loss may be involved in the pathogenesis of neuroblastoma and other cancers.