Aberrant expression of CPSF1 promotes head and neck squamous cell carcinoma via regulating alternative splicing

Akihiro Sakai, Mizuo Ando, Takahito Fukusumi, Shuling Ren, Chao Liu, Jesse Qualliotine, Sunny Haft, Sayed Sadat, Yuki Saito, Theresa W. Guo, Guorong Xu, Roman Sasik, Kathleen M. Fisch, J. Silvio Gutkind, Elana J. Fertig, Alfredo A. Molinolo, Joseph A. Califano

Research output: Contribution to journalArticle

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.

Original languageEnglish (US)
Article numbere0233380
JournalPloS one
Volume15
Issue number5
DOIs
StatePublished - May 2020

ASJC Scopus subject areas

  • Biochemistry, Genetics and Molecular Biology(all)
  • Agricultural and Biological Sciences(all)
  • General

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    Sakai, A., Ando, M., Fukusumi, T., Ren, S., Liu, C., Qualliotine, J., Haft, S., Sadat, S., Saito, Y., Guo, T. W., Xu, G., Sasik, R., Fisch, K. M., Gutkind, J. S., Fertig, E. J., Molinolo, A. A., & Califano, J. A. (2020). Aberrant expression of CPSF1 promotes head and neck squamous cell carcinoma via regulating alternative splicing. PloS one, 15(5), [e0233380]. https://doi.org/10.1371/journal.pone.0233380