Deficiencies in Chfr and Mlh1 synergistically enhance tumor susceptibility in mice

Abstract

Genetic instability, which leads to an accumulation of various genetic abnormalities, has been considered an essential component of the human neoplasic transformation process. However, the molecular basis of genomic instability during tumorigenesis remains incompletely understood. Growing evidence indicates that checkpoint with forkhead and ring finger domains (CHFR), a recently identified mitotic checkpoint protein, plays an important role in maintaining chromosome integrity and functions as a tumor suppressor. In this study, we used high-throughput technology to conduct gene expression profiling of human colon cancers and found that loss of CHFR expression frequently occurred in colon cancers with high microsatellite instability (MSI-H). Downregulation of CHFR expression was closely associated with overexpression of Aurora A, an important mitotic kinase. Mice with deficiencies in both Chfr and Mlh1 (the gene that encodes the DNA mismatch-repair protein Mlh1) displayed dramatically higher incidence of spontaneous tumors relative to mice deficient for only one of these genes. These results suggest that defects in both Chfr and Mlh1 synergistically increase predisposition to tumorigenesis.

CHFR: a key checkpoint component implicated in a wide range of cancers

“…The association between CHFR and Aurora A led to the ubiquitination of Aurora A and its destabilization in mouse embryo fibroblast cells in the presence of stress agents [26]. This is consistent with observations showing an inverse relationship between loss of CHFR function and Aurora A levels in CHFR -/-mouse embryonic fibroblasts (MEFs) [26], prostate [13] and breast [13,25] cancer cell lines as well as colorectal cancer samples [27].…”

High-definition CpG methylation of novel genes in gastric carcinogenesis identified by next-generation sequencing

“…37,38 As observed in our study, CHFR methylation is often associated with microsatelliteunstable gastric cancers 39 and genetic inactivation of both MLH1 and CHFR in mice resulted in much increased susceptibility to tumor development including gastrointestinal cancers. 40 In our study, among the novel genes identified to be hypermethylated in gastric cancer, BRINP1 and SGCE showed significant correlation of expression with survival in gastric cancer. BRINP1 (BMP/RA-induced neural specific protein-1) is induced during differentiation of peripheral neurons and overexpression of BRINPs was shown to suppress cell cycle progression in non-neural cells, suggesting a possible tumor suppressor role.…”

CHFR Promoter Methylation Indicates Poor Prognosis in Stage II Microsatellite Stable Colorectal Cancer

“…Although both CHFR and MLH1 contribute to genomic integrity, they function through different mechanisms. CHFR deficiency triggers mild CIN and MLH1 deficiency leading to MSI (56). Recent data from Oh and colleagues 2009 (57) indicate that, in vitro, CHFR binds and downregulates HDAC1 thereby downregulating cyclin-dependent kinase inhibitor 1 and the metastasis suppressors, KAI1 and Cadherin-1.…”