Faculty, Staff and Student Publications
Hereditary Retinoblastoma iPSC Model Reveals Aberrant Spliceosome Function Driving Bone Malignancies
Publication Date
4-19-2022
Journal
Proceedings of the National Academy of Sciences of the United States of America
Abstract
The RB1 gene is frequently mutated in human cancers but its role in tumorigenesis remains incompletely defined. Using an induced pluripotent stem cell (iPSC) model of hereditary retinoblastoma (RB), we report that the spliceosome is an up-regulated target responding to oncogenic stress in RB1-mutant cells. By investigating transcriptomes and genome occupancies in RB iPSC–derived osteoblasts (OBs), we discover that both E2F3a, which mediates spliceosomal gene expression, and pRB, which antagonizes E2F3a, coregulate more than one-third of spliceosomal genes by cobinding to their promoters or enhancers. Pharmacological inhibition of the spliceosome in RB1-mutant cells leads to global intron retention, decreased cell proliferation, and impaired tumorigenesis. Tumor specimen studies and genome-wide TCGA (The Cancer Genome Atlas) expression profile analyses support the clinical relevance of pRB and E2F3a in modulating spliceosomal gene expression in multiple cancer types including osteosarcoma (OS). High levels of pRB/E2F3a–regulated spliceosomal genes are associated with poor OS patient survival. Collectively, these findings reveal an undiscovered connection between pRB, E2F3a, the spliceosome, and tumorigenesis, pointing to the spliceosomal machinery as a potentially widespread therapeutic vulnerability of pRB-deficient cancers.
Keywords
Bone Neoplasms, Carcinogenesis, E2F3 Transcription Factor, Gene Expression Regulation, Neoplastic, Genes, Retinoblastoma, Humans, Induced Pluripotent Stem Cells, Mutation, Osteosarcoma, Retinal Neoplasms, Retinoblastoma, Retinoblastoma Binding Proteins, Spliceosomes, Ubiquitin-Protein Ligases
DOI
10.1073/pnas.2117857119
PMID
35412907
PMCID
PMC9169787
PubMedCentral® Posted Date
4-11-2022
PubMedCentral® Full Text Version
Post-print
Published Open-Access
yes
Included in
Bioinformatics Commons, Biomedical Informatics Commons, Medical Sciences Commons, Oncology Commons
