Reduced SKP1 and CUL1 expression underlies increases in Cyclin E1 and chromosome instability in cellular precursors of high-grade serous ovarian cancer

Chloe Camille Lepage,Ally Catherina Farrell,Zelda Lichtensztejn,Nicole Marie Neudorf,Mark William Nachtigal,Michaela Cora Lynn Palmer,Kirk James Mcmanus

doi:10.1038/s41416-021-01317-w

Abstract

BackgroundHigh-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.MethodsThis 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.ResultsSingle-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.ConclusionsThese data identify SKP1 and CUL1 as novel CIN genes in HGSOC precursor cells that may drive early aetiological events contributing to HGSOC development.

Highlights

High-grade serous ovarian cancer (HGSOC) is the most common and lethal ovarian cancer histotype
Determining the prevalence of diminished SKP1 or CUL1 expression in HGSOC To begin to assess the potential relevance of SKP1 or CUL1 alterations in cancer, the frequency of SKP1 or CUL1 copy number losses was assessed using TCGA data obtained for 12 common cancer types (Fig. 1a).[50,51]
A single HGSOC patient sample harbouring a SKP1 deep deletion was identified, and this alteration was mutually exclusive with Cyclin E1 gene (CCNE1) amplification

Summary

Introduction

High-grade serous ovarian cancer (HGSOC) is the most common and lethal ovarian cancer histotype. 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. High-grade serous ovarian cancer (HGSOC) is the most common histotype of epithelial ovarian cancer, accounting for ~70% of all diagnoses.[1,2] Owing to the lack of early detection methods, most women are diagnosed at late stages (~51% and ~29% at stages III and IV, respectively,3) and are typically treated with surgical debulking and neoadjuvant or adjuvant chemotherapy.

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Conclusion