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

Guillermo Aldave
Marisol Gonzalez-Huarriz
Angel Rubio
Juan Pablo Romero
Datta Ravi
Belén Miñana
Mar Cuadrado-Tejedor
Ana García-Osta
Roel G W Verhaak, The Jackson Laboratory
Enric Xipell
Naiara Martinez-Vélez
Arlet Acanda de la Rocha
Montserrat Puigdelloses
Marc García-Moure
Miguel Marigil
Jaime Gállego Pérez-Larraya
Oskar Marín-Bejar
Maite Huarte
Maria Stella Carro
Roberto Ferrarese
Cristobal Belda-Iniesta
Angel Ayuso
Ricardo Prat-Acín
Fernando Pastor
Ricardo Díez-Valle
Sonia Tejada
Marta M Alonso

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.

Neuro Oncol 2018 Jan 24 [Epub ahead of print]