Evaluating the impact diminished SKP1 and CUL1 expression have on chromosome instability and high-grade serous ovarian cancer pathogenesis
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Date
2019-12-17
Authors
Lepage, Chloe C.
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Abstract
High-grade serous ovarian cancer (HGSOC) is the most common and lethal ovarian cancer subtype. Chromosome instability (CIN; an increased rate of chromosome gains and losses) is believed to play a fundamental role in the development and evolution of HGSOC. The current study aims to evaluate the underlying mechanisms responsible for inducing CIN in HGSOC. Importantly, overexpression of Cyclin E1 protein induces CIN and genomic amplification contributes to HGSOC pathogenesis in ~20% of patients. Misregulation of Cyclin E1 at the protein level (i.e. aberrant protein turnover) is also expected to be causally linked to CIN and HGSOC development, but has never been evaluated in this context. Cyclin E1 levels are normally regulated in a cell cycle-dependent manner by the SCF (SKP1-CUL1-FBOX) complex, an E3 ubiquitin ligase that includes the proteins SKP1 and CUL1. Conceptually, loss of SCF complex function stemming from diminished SKP1 or CUL1 expression is predicted to underlie increases in Cyclin E1 protein levels and induce CIN. This study evaluates the impact of diminished SKP1 or CUL1 expression in a fallopian tube secretory epithelial cell model (a cell of origin for HGSOC) using two complementary approaches (siRNA and CRISPR/Cas9). Single-cell quantitative imaging microscopy approaches were employed to evaluate changes in CIN-associated phenotypes in response to diminished SKP1 or CUL1 expression. Our data identify SKP1 and CUL1 as novel CIN genes in HGSOC precursor cells that may contribute to the early development and pathogenesis of HGSOC.
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Keywords
High-grade serous ovarian cancer, Chromosome instability, Biochemistry, Genetics, Cancer, SCF complex, Cellular transformation
Citation
Lepage, C.C., Morden, C.R., Palmer, M.C.L., Nachtigal, M.W., and McManus, K.J. Detecting Chromosome Instability in Cancer: Approaches to Resolve Cell-to-Cell Heterogeneity. Cancers. 11, (2019).