LOH on 10p14-p15 targets the PFKFB3 gene locus in human glioblastomas

Loss of heterozygosity (LOH) on chromosome arm 10p is very common in high-grade gliomas and is, among others, concentrated on the region 10p14-p15. Presence of multiple tumor suppressor genes is assumed, but until now only Krüpple-like transcription factor 6 (KLF6) has been suggested as possible target of LOH in this region. On the basis of the fact that the splice variant 4 (UBI2K4) of the PFKFB3 gene, located in 10p15.1, inhibits the anchorage-independent growth of U87 glioblastoma cells, we hypothesized that PFKFB3 is a target gene of LOH in glioblastomas. In this study, we analyzed 40 glioblastomas for LOH in 10p15, including the PFKFB3 and KLF6 loci, by PCR-based microsatellite analysis. We detected LOH of PFKFB3 in 55% (22/40) of glioblastomas. LOH of KLF6, mapped 2.5 cM telomerically to the PFKFB3 locus, was not stringently correlated to the PFKFB3 LOH. The allelic deletion of PFKFB3 resulted in a decrease of PFKFB3 mRNA level accompanied by a lower PFKFB3 protein level. The expression of growth-inhibiting splice variant UBI2K4 was effectively reduced in glioblastomas with PFKFB3 LOH and a positive correlation with overall PFKFFB3 expression was observed. The PFKFB3 LOH as well as the resulting low UBI2K4 expression level was associated with a poor prognosis of glioblastoma patients. We conclude that LOH on 10p14-p15 in glioblastomas targets PFKFB3 and in particular splice variant UBI2K4, a putative tumor suppressor protein in glioblastomas.