Reduced SKP2 Expression Adversely Impacts Genome Stability and Promotes Cellular Transformation in Colonic Epithelial Cells

Abstract

Despite the high morbidity and mortality rates associated with colorectal cancer (CRC), the underlying molecular mechanisms driving CRC development remain largely uncharacterized. Chromosome instability (CIN), or ongoing changes in chromosome complements, occurs in ~85% of CRCs and is a proposed driver of cancer development, as the genomic changes imparted by CIN enable the acquisition of karyotypes that are favorable for cellular transformation and the classic hallmarks of cancer. Despite these associations, the aberrant genes and proteins driving CIN remain elusive. SKP2 encodes an F-box protein, a variable subunit of the SKP1-CUL1-F-box (SCF) complex that selectively targets proteins for polyubiquitylation and degradation. Recent data have identified the core SCF complex components (SKP1, CUL1, and RBX1) as CIN genes; however, the impact reduced SKP2 expression has on CIN, cellular transformation, and oncogenesis remains unknown. Using both short- small interfering RNA (siRNA) and long-term (CRISPR/Cas9) approaches, we demonstrate that diminished SKP2 expression induces CIN in both malignant and non-malignant colonic epithelial cell contexts. Moreover, temporal assays reveal that reduced SKP2 expression promotes cellular transformation, as demonstrated by enhanced anchorage-independent growth. Collectively, these data identify SKP2 as a novel CIN gene in clinically relevant models and highlight its potential pathogenic role in CRC development.