BCL9L Dysfunction Impairs Caspase-2 Expression Permitting Aneuploidy Tolerance in Colorectal Cancer.

Abstract

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.

• Authors: Carlos López-García, Laurent Sansregret, Enric Domingo, Nicholas McGranahan, Sebastijan Hobor, Nicolai Juul Birkbak, Stuart Horswell, Eva Grönroos, Francesco Favero, Andrew J Rowan, Nicholas Matthews, Sharmin Begum, Benjamin Phillimore, Rebecca Burrell, Dahmane Oukrif, Bradley Spencer-Dene, Michal Kovac, Gordon Stamp, Aengus Stewart, Havard Danielsen, Marco Novelli, Ian Tomlinson, Charles Swanton
• Journal: Cancer cell (Cancer Cell) Vol. 31 Issue 1 Pg. 79-93 (01 09 2017) ISSN: 1878-3686 [Electronic] United States
• PMID: 28073006 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)
• Copyright: Copyright © 2017 The Francis Crick Institute. Published by Elsevier Inc. All rights reserved.

Chemical References

• BCL9L protein, human
• BH3 Interacting Domain Death Agonist Protein
• BID protein, human
• DNA-Binding Proteins
• TP53 protein, human
• Transcription Factors
• Tumor Suppressor Protein p53
• MDM2 protein, human
• Proto-Oncogene Proteins c-mdm2
• CASP2 protein, human
• Caspase 2
• Cysteine Endopeptidases

Topics

• Aged
• Aged, 80 and over
• Aneuploidy
• Animals
• BH3 Interacting Domain Death Agonist Protein (physiology)
• Caspase 2 (analysis, physiology)
• Chromosome Segregation
• Colorectal Neoplasms (genetics)
• Cysteine Endopeptidases (analysis, physiology)
• DNA-Binding Proteins (genetics, physiology)
• HCT116 Cells
• Humans
• Mice
• Middle Aged
• Mutation
• Proto-Oncogene Proteins c-mdm2 (physiology)
• Transcription Factors (genetics, physiology)
• Tumor Suppressor Protein p53 (physiology)