Loss of HLTF function promotes intestinal carcinogenesis

To address the role of loss of HLTF function in the development of intestinal cancer, we generated Hltf deficient mice. These mutant mice showed normal development, and did not develop intestinal tumors, indicating that loss of Hltf function by itself is insufficient to induce the formation of intestinal cancer. On the Apcmin/+ mutant background, Hltf- deficiency was found to significantly increase the formation of intestinal adenocarcinoma and colon cancers. Cytogenetic analysis of colon tumor cells from Hltf -/-/Apcmin/+ mice revealed a high incidence of gross chromosomal instabilities, including Robertsonian fusions, chromosomal fragments and aneuploidy. None of these genetic alterations were observed in the colon tumor cells derived from Apcmin/+ mice. Increased tumor growth and genomic instability was also demonstrated in HCT116 human colon cancer cells in which HLTF expression was significantly decreased.Taken together, our results demonstrate that loss of HLTF function promotes the malignant transformation of intestinal or colonic adenomas to carcinomas by inducing genomic instability. Our findings highly suggest that epigenetic inactivation of HLTF, as found in most human colon cancers, could play an important role in the progression of colon tumors to malignant cancer.Human colon cancer is the second leading cause of cancer-related death in developed countries. About 50% of the Western population develops adenomatous polyps (a benign colon tumor) by the age of 70, and the lifetime risk for colon cancer is estimated to be 5% [1]. The formation of colon cancer involves a multiple-step process, starting from a small adenomatous polyp and followed by the development of a large adenoma with dysplasia that ultimately leads to the formation of invasive carcinoma (see the recent review by Fearon ER [2]). It is widely accepted that most human colon cancers are initiated by the inactivation of the Adenomatous Polyposis Coli (APC)/Wnt signaling pathway and then progre