The aberrant splicing of BAF45d links splicing regulation and transcription in glioblastoma
Aldave G (1), Gonzalez-Huarriz M (2,3,4), Rubio A (5), Romero JP (5), Ravi D (5), Miñana B (6), Cuadrado-Tejedor M (3,7,8), García-Osta A (3,7), Verhaak R (9, 10), Xipell E (2,3,4), Martinez-Vélez N (2,3,4), Acanda de la Rocha A (2,3,4), Puigdelloses M (2,3,4), García-Moure M (2,3,4), Marigil M (2,3,4), Gállego Pérez-Larraya J (2,3,4), Marín-Bejar O (3,11), Huarte M (3,11), Carro MS (12), Ferrarese R (12), Belda-Iniesta C (13), Ayuso A (13,14), Prat-Acín R (15), Pastor F (3,16), Díez-Valle R (3,4,17), Tejada S (3,4,17), Alonso MM (2,3,4).
(1) Division of Pediatric Neurosurgery, Department of Surgery, Texas Children´s Hospital, Department of Neurosurgery, Baylor College of Medicine. Houston, Texas, USA.
(2) Department of Pediatrics, University Hospital of Navarra, Pamplona, Navarra, Spain.
(3) The Health Research Institute of Navarra (IDISNA), Pamplona, Navarra, Spain.
(4) Program in Solid Tumors, Foundation for the Applied Medical Research, Pamplona, Navarra, Spain.
(5) CEIT and TECNUN, University of Navarra, San Sebastian, Spain.
(6) Centre de Regulació Genòmica (CRG), The Barcelona Institute of Science and Technology, Barcelona, Spain, Universitat Pompeu-Fabra, Barcelona, Spain.
(7) Neurobiology of Alzheimer´s Disease, Neurosciences Division, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.
(8) Anatomy Department, School of Medicine, University of Navarra, Pamplona, Spain.
(9) Department of Genomic Medicine, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
(10) Department of Bioinformatics and Computational Biology, Division of Quantitative Sciences, The University of Texas MD Anderson Cancer Center, Houston, Texas, USA.
(11) Department of Gene Therapy and Regulation of Gene Expression, Center for Applied Medical Research, CIMA, University of Navarra, Pamplona, Spain.
(12) Department of Neurosurgery (Neurocenter) Universitätsklinikum Freiburg, Freiburg, Germany.
(13) Fundación de Investigación HM Hospitales, Grupo HM, Spain.
(14) Facultad de Medicina, Universidad CEU-San Pablo, Madrid, Spain.
(15) Department of Neurosurgery, Hospital Universitario y Politécnico La Fe, Valencia, Spain.
(16) Program of Molecular Therapies, Aptamer Unit, Centro de Investigación Médica Aplicada (CIMA), Pamplona, Spain.
(17) Department of Neurosurgery, University Hospital of Navarra, Pamplona, Navarra, Spain.
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.
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.
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.
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.
CITATION Neuro Oncol. 2018 Jan 24. doi: 10.1093/neuonc/noy007