TY - JOUR
T1 - Aberrant expression of CPSF1 promotes head and neck squamous cell carcinoma via regulating alternative splicing
AU - Sakai, Akihiro
AU - Ando, Mizuo
AU - Fukusumi, Takahito
AU - Ren, Shuling
AU - Liu, Chao
AU - Qualliotine, Jesse
AU - Haft, Sunny
AU - Sadat, Sayed
AU - Saito, Yuki
AU - Guo, Theresa W.
AU - Xu, Guorong
AU - Sasik, Roman
AU - Fisch, Kathleen M.
AU - Gutkind, J. Silvio
AU - Fertig, Elana J.
AU - Molinolo, Alfredo A.
AU - Califano, Joseph A.
N1 - Publisher Copyright:
© 2020 Sakai et al. This is an open access article distributed under the terms of the Creative Commons Attribution License, which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
PY - 2020/5
Y1 - 2020/5
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85085155723&partnerID=8YFLogxK
UR - http://www.scopus.com/inward/citedby.url?scp=85085155723&partnerID=8YFLogxK
U2 - 10.1371/journal.pone.0233380
DO - 10.1371/journal.pone.0233380
M3 - Article
C2 - 32437477
AN - SCOPUS:85085155723
SN - 1932-6203
VL - 15
JO - PLoS One
JF - PLoS One
IS - 5
M1 - e0233380
ER -
