BCL9L depletion reduces CASP2 levels to promote aneuploidy tolerance in colon tumors.
Major finding: BCL9L depletion reduces CASP2 levels to promote aneuploidy tolerance in colon tumors.
Mechanism: Reduced BCL9L inhibits TCF4-mediated CASP2 transcription to decrease cleavage of MDM2 and BID.
Impact: Therapeutic targeting of aneuploidy tolerance mechanisms may inhibit tumor evolution and heterogeneity.
Genomic instability due to the missegregation of chromosomes, termed chromosomal instability (CIN), results in aneuploidy, frequently occurs in cancer, and drives intratumoral heterogeneity. Cancer cells exhibit aneuploidy tolerance, and potential mechanisms underlying aneuploidy tolerance include TP53 mutations and maintenance of protein stoichiometry. Microsatellite-stable (MSS) colorectal tumors exhibit a wide range of aneuploidy and CIN, and aneuploid MSS tumors frequently harbor TP53 mutations. To identify the genetic determinants of CIN in MSS colorectal tumors, López-García and colleagues performed whole-exome sequencing (WES) of 17 MSS colorectal adenocarcinomas, 10 of which were aneuploid, and 8 aneuploid MSS cell lines. WES showed that six aneuploid MSS tumors harbored inactivating mutations or LOH of the β-catenin transcriptional co-factor B-cell CLL/lymphoma 9-like (BCL9L). Aneuploid MSS tumors were also enriched for TP53 mutations as expected. Analysis of The Cancer Genome Atlas (TCGA) MSS colorectal cancer cohort demonstrated the frequent co-occurrence of deleterious BCL9L alterations and TP53 mutations in MSS colon tumors. Truncating BCL9L mutations generated by CRISPR/Cas9 induced aneuploidy tolerance in wild-type TP53 and TP53-null cells in vitro, and ablation of BCL9L promoted intratumoral heterogeneity in mouse xenograft models. Depletion of BCL9L in aneuploid-induced wild-type TP53 cells prevented TP53 accumulation, decreased levels of caspase-2 (CASP2), which cleaves MDM2 to produce MDM2-p60, and reduced the levels of MDM2-p60, which stabilizes TP53. Further, depletion of BCL9L in aneuploid-induced TP53 -null cells reduced the formation of the cleavage product of the CASP2 substrate BH3 interacting domain death agonist (tBID), which is required for death receptor–induced apoptosis. Chromatin immunoprecipitation assays demonstrated the interaction of TCF4 with the CASP2 promoter, and inhibition of the β-catenin–TCF4 interaction reduced CASP2 mRNA and protein expression. Together, these results elucidate the mechanism by which loss-of-function BCL9L alterations promote aneuploidy tolerance in colon tumors and suggest that mechanisms driving aneuploidy tolerance may be potential therapeutic targets.
López-García C, Sansregret L, Domingo E, McGranahan N, Hobor S, Birkbak NJ, et al. BCL9L dysfunction impairs caspase-2 expression permitting aneuploidy tolerance in colorectal cancer. Cancer Cell 2017;31:79–93.
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