Role of an Alternatively Spliced KCNMA1 Variant in Glioma Growth

Abstract

Gliomas develop genetic traits to rapidly form aggressive phenotypes. Hence, man- agement of gliomas is complicated and difficult. Besides genetic aberrations such as oncogenic copy number variation and mutations, alternative mRNA splicing triggers prooncogenic episodes in many cancers. In gliomas, we found alternative splicing at the KCNMA transcription process. KCNMA1 encodes the pore forming α-subunit of large-conductance calcium-activated voltage-sensitive potassium (BK Ca ) channels. These channels play critical role in glioma invasion and proliferation. We identified a novel KCNMA1 mRNA splice variant with a deletion of 108 base pairs ( KCNMA1v ) mostly overexpressed in high grade gliomas. We found that KCNMA1 alternative pre-mRNA splicing enhanced glioma growth, progression and diffusion. The role of KCNMA1 and its splicing as a critical posttranscriptional regulator of BK Ca channel expression is pre- sented in this chapter. Our research implies that high grade gliomas express KCNMA1v and BK Ca channel isoform to accelerate growth and transformation to glioblastoma multiforme (GBM). We demonstrated that tumors hardly develop in mice injected with KCNMA1v transfected cell line expressing short-hairpin RNA (shRNA) compared to mice injected with KCNMA1v transected glioma cells. We conclude that targeting the KCNMA1 variants may be a clinically beneficial strategy to prevent or at least slow down glioma transformation to GBM .