British journal of cancer · 2021
Reduced SKP1 and CUL1 expression underlies increases in Cyclin E1 and chromosome instability in cellular precursors of high-grade serous ovarian cancer.
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Lepage Chloe Camille, Palmer Michaela Cora Lynn, Farrell Ally Catherina, Neudorf Nicole Marie, Lichtensztejn Zelda, Nachtigal Mark William, McManus Kirk James
Аннотация
BACKGROUND: High-grade serous ovarian cancer (HGSOC) is the most common and lethal ovarian cancer histotype. 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. Importantly, overexpression of Cyclin E1 protein induces CIN, and genomic amplification of CCNE1 contributes to HGSOC pathogenesis in ~20% of patients. 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, diminished SKP1 or CUL1 expression is predicted to underlie increases in Cyclin E1 levels and induce CIN.
METHODS: This study employs fallopian tube secretory epithelial cell models to evaluate the impact diminished SKP1 or CUL1 expression has on Cyclin E1 and CIN in both short-term (siRNA) and long-term (CRISPR/Cas9) studies.
RESULTS: Single-cell quantitative imaging microscopy approaches revealed changes in CIN-associated phenotypes and chromosome numbers and increased Cyclin E1 in response to diminished SKP1 or CUL1 expression.
CONCLUSIONS: These data identify SKP1 and CUL1 as novel CIN genes in HGSOC precursor cells that may drive early aetiological events contributing to HGSOC development.
METHODS: This study employs fallopian tube secretory epithelial cell models to evaluate the impact diminished SKP1 or CUL1 expression has on Cyclin E1 and CIN in both short-term (siRNA) and long-term (CRISPR/Cas9) studies.
RESULTS: Single-cell quantitative imaging microscopy approaches revealed changes in CIN-associated phenotypes and chromosome numbers and increased Cyclin E1 in response to diminished SKP1 or CUL1 expression.
CONCLUSIONS: These data identify SKP1 and CUL1 as novel CIN genes in HGSOC precursor cells that may drive early aetiological events contributing to HGSOC development.