Publication Date
8-1-2024
Journal
Nature Cell Biology
DOI
10.1038/s41556-024-01460-5
PMID
39025928
PMCID
PMC11321995
PubMedCentral® Posted Date
7-18-2024
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Keywords
Otx Transcription Factors, Medulloblastoma, Alternative Splicing, Humans, Neoplastic Stem Cells, Cerebellar Neoplasms, Animals, Gene Expression Regulation, Neoplastic, Cell Line, Tumor, Mice, Cell Proliferation, Cancer stem cells, Differentiation, CNS cancer
Abstract
OTX2 is a transcription factor and known driver in medulloblastoma (MB), where it is amplified in a subset of tumours and overexpressed in most cases of group 3 and group 4 MB. Here we demonstrate a noncanonical role for OTX2 in group 3 MB alternative splicing. OTX2 associates with the large assembly of splicing regulators complex through protein-protein interactions and regulates a stem cell splicing program. OTX2 can directly or indirectly bind RNA and this may be partially independent of its DNA regulatory functions. OTX2 controls a pro-tumorigenic splicing program that is mirrored in human cerebellar rhombic lip origins. Among the OTX2-regulated differentially spliced genes, PPHLN1 is expressed in the most primitive rhombic lip stem cells, and targeting PPHLN1 splicing reduces tumour growth and enhances survival in vivo. These findings identify OTX2-mediated alternative splicing as a major determinant of cell fate decisions that drive group 3 MB progression.
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