Journal article
BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer
The Francis Crick Institute1
University of Oxford2
Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark3
Cancer Systems Biology, Center for Biological Sequence Analysis, Department of Systems Biology, Technical University of Denmark4
Department of Systems Biology, Technical University of Denmark5
University College London6
Wellcome Trust Centre for Human Genetics7
Oslo University Hospital8
Chromosomal instability (CIN) contributes to cancer evolution, intratumor heterogeneity, and drug resistance. CIN is driven by chromosome segregation errors and a tolerance phenotype that permits the propagation of aneuploid genomes. Through genomic analysis of colorectal cancers and cell lines, we find frequent loss of heterozygosity and mutations in BCL9L in aneuploid tumors.
BCL9L deficiency promoted tolerance of chromosome missegregation events, propagation of aneuploidy, and genetic heterogeneity in xenograft models likely through modulation of Wnt signaling. We find that BCL9L dysfunction contributes to aneuploidy tolerance in both TP53-WT and mutant cells by reducing basal caspase-2 levels and preventing cleavage of MDM2 and BID.
Efforts to exploit aneuploidy tolerance mechanisms and the BCL9L/caspase-2/BID axis may limit cancer diversity and evolution.
| Language: | English |
|---|---|
| Publisher: | Cell Press |
| Year: | 2016 |
| Pages: | 79-93 |
| ISSN: | 18783686 and 15356108 |
| Types: | Journal article |
| DOI: | 10.1016/j.ccell.2016.11.001 |
BCL9L BID SDG 3 - Good Health and Well-being aneuploidy tolerance caspase-2 chromosomal instability chromosome segregation errors colorectal cancer evolution intratumor heterogeneity mitotic checkpoint p53
Aged Aged, 80 and over Aneuploidy Animals BCL9L protein, human BH3 Interacting Domain Death Agonist Protein BID protein, human CASP2 protein, human Caspase 2 Chromosome Segregation Colorectal Neoplasms Cysteine Endopeptidases DNA-Binding Proteins HCT116 Cells Humans MDM2 protein, human Mice Middle Aged Mutation Proto-Oncogene Proteins c-mdm2 TP53 protein, human Transcription Factors Tumor Suppressor Protein p53
