Suppression of ELF4 in ulcerative colitis predisposes host to colorectal cancer
Ulcerative colitis (UC) is a chronic inflammatory bowel disease (IBD), characterized by relapsing and remitting colon mucosal inflammation. For patients suffering from UC, a higher risk of colon cancer has been widely recognized. Here we found that Elf4-/- mice developed colon tumors with 3 cycles of DSS treatment alone. We further showed ELF4 suppression was prevalent in both UC patients and DSS-induced mice model and this suppression was caused by promoter region methylation. ELF4, upon PARylation by PARP1, transcriptionally regulated multiple DNA damage repair (DDR) machinery components. Consistently, ELF4 deficiency leads to more severe DNA damage both in vitro and in vivo. Oral administration of montmorillonite powder can prevent the reduction of ELF4 in DSS-induced colitis model and lower the risk of colon tumor development during AOM-DSS-induced colitis. These data provided additional mechanism of colitis-associated cancer (CAC) initiation and supported the “epigenetic priming model of tumor initiation”.