Open AccessAberrant expression of CPSF1 promotes head and neck squamous cell carcinoma via regulating alternative splicing
Author(s) -
Akihiro Sakai,
Mizuo Ando,
Takahito Fukusumi,
Shuling Ren,
Chao Liu,
Jesse R. Qualliotine,
Sunny Haft,
Sayed Sadat,
Yuki Saito,
Theresa Guo,
Guiyin Xu,
Roman Šášik,
Kathleen M. Fisch,
J. Silvio Gutkind,
Elana J. Fertig,
Alfredo A. Molinolo,
Joseph A. Califano
Publication year - 2020
Publication title -
plos one
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 0.99
H-Index - 332
ISSN - 1932-6203
DOI - 10.1371/journal.pone.0233380
Subject(s) - spliceosome , biology , head and neck squamous cell carcinoma , rna splicing , gene knockdown , alternative splicing , carcinogenesis , gene , cancer research , gene expression , regulation of gene expression , gene expression profiling , genetics , microbiology and biotechnology , rna , cancer , messenger rna , head and neck cancer
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.