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

Abstract

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.

Ubiquitin Proteasome Pathway Transcriptome in Epithelial Ovarian Cancer

“…The Cullin 4 CRLs have been reported to contribute to regulation of development, regulation of the cell cycle, regulation of DNA repair, and control of gene transcription [ 80 ]. Recently, Bungsy et al [ 81 ] and Lepage et al [ 82 ] assessed the impact of reduced expression of the SKP1-CUL1-F-box protein (SCF) E3 ubiquitin ligase complex members on chromosome instability in immortalized fallopian tube secretory epithelial cells. The SCF complex is composed of four protein subunits, three of which are invariable core components (RING box protein 1 (RBX1), S-phase kinase associated protein 1 (SKP1), and Cullin 1 (CUL1)) and a variable F-box protein that confers substrate specificity [ 83 ].…”

Cytotoxic capacity of a novel glycosylated antitumor ether lipid in chemotherapy-resistant high grade serous ovarian cancer in vitro and in vivo

“…HGSOC is a genetically unstable disease [ [24] , [25] , [26] , [27] ] characterized by a type of genomic instability called chromosome instability (CIN) [ [28] , [29] , [30] , [31] , [32] ]. CIN is defined by an increase in the rate at which whole chromosomes or large parts are gained or lost [33] , and is associated with intratumoral heterogeneity, poor patient outcome, and chemoresistance [ [33] , [34] , [35] , [36] , [37] , [38] ].…”

The SCF Complex Is Essential to Maintain Genome and Chromosome Stability

“…For example, mutation, misexpression, or misregulation of the adaptor protein, SKP1, is expected to be especially damaging as it would prevent proper SCF complex formation, F-box protein recruitment, protein target poly-ubiquitination, and proteolytic degradation, which would adversely impact key biological pathways, culminating in cellular dysfunction and disease development. Indeed, SKP1 copy number losses are suggested to be pathogenic driver events in colorectal and high-grade serous ovarian cancers [16,17]. Thus, understanding the role each member of the SCF complex in diverse cellular contexts will be critical to gain novel insight into disease pathogenesis, and may hold diagnostic and/or prognostic implications that will be valuable in the clinical management of diseases such as cancer [18,19].…”

“…To investigate this hypothesis, genetic and biochemical studies are required to fully realize the implications that SKP1, CUL1, and RBX1 dysfunction have for cell cycle misregulation, cellular dysfunction, genome instability, and tumorigenesis. Indeed, several genetic studies performed in malignant [17] and non-malignant [16] human contexts have established that reduced SKP1, CUL1, and RBX1 expression induces chromosome instability (CIN), a prevalent form of genome instability. Briefly, CIN is defined as an increase in the rate at which whole chromosomes or large chromosome fragments are gained or lost, and is an established driver of both genetic and cellular heterogeneity (reviewed in [19,75]).…”

“…If, as predicted, all three genes are essential, then further diminishing or inhibiting their residual expression and/or function below a specific threshold is expected to induce lethality. Still, this hypothetical systemic approach is not without risk as each gene was recently identified as a CIN gene [16,17,106] and CIN is an enabling hallmark associated with early (e.g., cellular transformation [76,77] and intra-tumoral heterogeneity [78][79][80]) and late (e.g., metastasis [81][82][83] and drug resistance [85,86]) etiological events. Thus, such a systemic approach is expected to induce side effects within the normal surrounding cells or tissues; however, if reduced expression or inhibition can be selectively delivered to the cancer cells, then a large therapeutic window is expected to open.…”