biostudies-literatureNeudorf NMCancerCare ManitobaResearch Manitoba/CancerCare ManitobaNatural Sciences and Engineering Research Council3731https://www.ebi.ac.uk/biostudies/studies/S-EPMC9738323biostudies-literatureUnknown11(23)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. <i>SKP2</i> 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 (<i>SKP1</i>, <i>CUL1</i>, and <i>RBX1</i>) as CIN genes; however, the impact reduced <i>SKP2</i> 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 <i>SKP2</i> expression induces CIN in both malignant and non-malignant colonic epithelial cell contexts. Moreover, temporal assays reveal that reduced <i>SKP2</i> expression promotes cellular transformation, as demonstrated by enhanced anchorage-independent growth. Collectively, these data identify <i>SKP2</i> as a novel CIN gene in clinically relevant models and highlight its potential pathogenic role in CRC development.CellsReduced <i>SKP2</i> Expression Adversely Impacts Genome Stability and Promotes Cellular Transformation in Colonic Epithelial Cells.PMC9738323Operating Grant (K.J.M.)Studentship (N.M.N.)K.J.M.; RGPIN: 2018-05007McManus KJLichtensztejn ZNeudorf NMThompson LLRazi TfalseReduced <i>SKP2</i> Expression Adversely Impacts Genome Stability and Promotes Cellular Transformation in Colonic Epithelial Cells.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. <i>SKP2</i> 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 (<i>SKP1</i>, <i>CUL1</i>, and <i>RBX1</i>) as CIN genes; however, the impact reduced <i>SKP2</i> 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 <i>SKP2</i> expression induces CIN in both malignant and non-malignant colonic epithelial cell contexts. Moreover, temporal assays reveal that reduced <i>SKP2</i> expression promotes cellular transformation, as demonstrated by enhanced anchorage-independent growth. Collectively, these data identify <i>SKP2</i> as a novel CIN gene in clinically relevant models and highlight its potential pathogenic role in CRC development.2022-01-01T00:00:00Z2022 Nov2025-04-19T06:37:20.095Z2025-04-19T06:37:20.095ZS-EPMC97383233649699010.3390/cells11233731