Abstract
Alternative mRNA splicing increases protein diversity, and alternative splicing events (ASEs) drive oncogenesis in multiple tumor types. However, the driving alterations that underlie the broad dysregulation of ASEs are incompletely defined. Using head and neck squamous cell carcinoma (HNSCC) as a model, we hypothesized that the genomic alteration of genes associated with the spliceosome may broadly induce ASEs across a broad range of target genes, driving an oncogenic phenotype. We identified 319 spliceosome genes and employed a discovery pipeline to identify 13 candidate spliceosome genes altered in HNSCC using The Cancer Genome Atlas (TCGA) HNSCC data. Phenotypic screens identified amplified and overexpressed CPSF1 as a target gene alteration that was validated in proliferation, colony formation, and apoptosis assays in cell line and xenograft systems as well as in primary HNSCC. We employed knockdown and overexpression assays followed by identification of ASEs regulated by CPSF1 overexpression to identify changes in ASEs, and the expression of these ASEs was validated using RNA from cell line models. Alterations in expression of spliceosome genes, including CPSF1, may contribute to HNSCC by mediating aberrant ASE expression.
Highlights
Head and neck squamous cell carcinomas (HNSCC) constitute the sixth most common cancer type in the world [1]
To investigate the relationship between the 319 genes and alternative splicing events (ASEs), a heatmap using unsupervised hierarchical clustering of the gene expression levels with ASE number was created for the samples in an human papillomavirus (HPV) positive HNSCC primary tumor cohort (Fig 1A)
We were able to identify a cluster of tumors with high ASE that was associated with spliceosome gene expression
Summary
Head and neck squamous cell carcinomas (HNSCC) constitute the sixth most common cancer type in the world [1]. The most important conventional risk factors for HNSCC are tobacco and excessive consumption of alcohol [2]. In addition to these factors, human papillomavirus (HPV) is recognized as an independent risk factor for oropharyngeal squamous cell carcinomas and cervical cancer [3]. Comprehensive examination of genomic alterations in HNSCC was reported by investigators from The Cancer Genome Atlas (TCGA) Research Network showed that many HNSCC have alterations in genes for growth factor receptors (EGFR, FGFR, IGFR, MET, ERBB2, and DDR2), signaling molecules (PIK3CA and HRAS), and regulation of genomic integrity and the cell cycle (TP53, CCND1). Only a few studies have investigated alternative splicing in HNSCC [10, 11]
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