Determining the impact diminished RBX1 expression has on chromosome stability in cancer
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Date
2019-12-19
Authors
Bungsy, Manisha
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Abstract
Chromosome instability (CIN) is an aberrant phenotype observed in nearly all cancer types including colorectal cancer and potentially, high-grade serous ovarian cancer (HGSOC). CIN is defined as an increase in the rate at which whole chromosomes, or large parts thereof, are gained or lost. In many cancer types, CIN is associated with cellular transformation, highly aggressive tumors, multi-drug resistance and poor patient outcome. Despite these associations, the molecular mechanisms underlying CIN remain largely unknown. Genomic amplification of Cyclin E1 (CCNE1) induces CIN and is a pathogenic event in ~22% of HGSOCs. Cyclin E1 is a cell cycle regulatory protein whose levels are tightly controlled by the SCF complex, an E3 ubiquitin ligase. The SCF complex is comprised of RBX1, SKP1, CUL1 and an FBox protein, and targets proteins like Cyclin E1 for degradation by the 26S proteasome. Remarkably, >80% of HGSOCs exhibit heterozygous loss of RBX1, which encodes the catalytic component of the SCF complex. Since RBX1 is a core component of the SCF complex, I hypothesise that its reduced expression is predicted to impair SCF complex function which may lead to the accumulation of oncogenic proteins like Cyclin E1. This suggests that aberrant turnover of oncoproteins such as Cyclin E1 may constitute an alternative pathway for inducing CIN and tumorigenesis. This study employs both transient (siRNA) and stable (CRISPR-Cas9) approaches to determine the impact of reduced RBX1 expression on CIN and Cyclin E1 levels. Through the CRISPR-Cas9 approach, this study specifically seeks to model early disease development by assessing the potential impact heterozygous loss of RBX1 may have on Cyclin E1 levels, CIN and cellular transformation in fallopian tube (FT) secretory epithelial cells, a cell of origin for HGSOC. Data gleaned from this study identify RBX1 as a novel CIN gene, which suggests that reduced RBX1 expression may contribute to early pathogenic events driving HGSOC development and progression.
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Biochemistry, Medical Genetics, Ovarian Cancer