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

Akihiro Sakai1,2, Mizuo Ando1, Takahito Fukusumi1

  • 1Moores Cancer Center, University of California San Diego, San Diego, California, United States of America.

Plos One
|May 22, 2020
PubMed

Insights

Genomic alterations in spliceosome genes, like CPSF1, drive alternative splicing events in head and neck squamous cell carcinoma (HNSCC). This dysregulation promotes cancer development by altering gene expression.

Area of Science:

  • Molecular Biology
  • Cancer Genomics
  • Oncogenesis

Background:

  • Alternative mRNA splicing generates protein diversity.
  • Alternative splicing events (ASEs) are implicated in oncogenesis across various tumor types.
  • The genomic drivers of ASE dysregulation remain incompletely understood.

Purpose of the Study:

  • To investigate the hypothesis that alterations in spliceosome genes broadly induce ASEs in head and neck squamous cell carcinoma (HNSCC).
  • To identify specific spliceosome genes driving oncogenesis in HNSCC.

Main Methods:

  • Utilized The Cancer Genome Atlas (TCGA) HNSCC data to identify altered spliceosome genes.
  • Conducted phenotypic screens to identify candidate genes.
  • Performed knockdown and overexpression assays to assess the impact of CPSF1 on ASEs.
  • Validated findings in cell line and xenograft models, as well as primary HNSCC samples.

Main Results:

  • Identified 13 candidate spliceosome genes altered in HNSCC.
  • CPSF1 was identified as an amplified and overexpressed gene.
  • CPSF1 overexpression significantly altered ASEs, impacting proliferation, colony formation, and apoptosis.
  • Aberrant ASE expression mediated by CPSF1 was validated in HNSCC models.

Conclusions:

  • Genomic alterations in spliceosome genes, particularly CPSF1, contribute to HNSCC development.
  • CPSF1-mediated aberrant ASE expression is a key mechanism driving oncogenesis in HNSCC.
  • Targeting spliceosome gene alterations may offer novel therapeutic strategies for HNSCC.

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