The aberrant splicing of BAF45d links splicing regulation and transcription in glioblastoma

Abstract

Background

Glioblastoma, the most aggressive primary brain tumor, is a genetically heterogeneous tumor. Alternative spicing (AS) plays a key role in numerous pathologies, including cancer. The objective of our study was to determine whether aberrant AS could play a role in the malignant phenotype of glioma and to understand the mechanism underlying its aberrant regulation.

Methods

We obtained surgical samples from patients with glioblastoma who underwent 5-aminolevulinic fluorescence-guided surgery. Biopsies were taken from the tumor center as well as from adjacent normal-appearing tissue. We used a global splicing array to identify candidate genes aberrantly spliced in these glioblastoma samples. Mechanistic and functional studies were performed to elucidate the role of our top candidate splice variant, BAF45d, in glioblastoma.

Results

BAF45d is part of the switch/sucrose non-fermentable (SWI/SNF) complex and plays a key role in the development of the CNS. The BAF45d/6A-isoform is present in 85% of over 200 glioma samples that have been analyzed, and contributes to the malignant glioma phenotype through the maintenance of an undifferentiated cellular state. We demonstrate that BAF45d splicing is mediated by polypyrimidine-tract-binding protein 1 (PTBP1) and that BAF45d regulates PTBP1, uncovering a reciprocal interplay between RNA splicing regulation and transcription.

Conclusions

Our data indicate that AS is a mechanism that contributes to the malignant phenotype of glioblastoma. Understanding the consequences of this biological process will uncover new therapeutic targets for this devastating disease.