Loss of HLTF function promotes intestinal carcinogenesis

Abstract

BackgroundHLTF (Helicase-like Transcription Factor) is a DNA helicase protein homologous to the SWI/SNF family involved in the maintenance of genomic stability and the regulation of gene expression. HLTF has also been found to be frequently inactivated by promoter hypermethylation in human colon cancers. Whether this epigenetic event is required for intestinal carcinogenesis is unknown.ResultsTo 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.ConclusionTaken 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.

The helicase-like transcription factor (HLTF) in cancer: loss of function or oncomorphic conversion of a tumor suppressor?

“…This HLTF function in DNA repair correlates with the transcriptome alterations observed upon Hltf gene inactivation in the mouse [24,27]. Moreover, such a link between HLTF function and genome integrity was highlighted in cancers such as (a) in colon carcinogenesis, where an increased genomic instability was observed in another Hltf null mouse model [84] and (b) in cervical cancers, where radioresistance was associated with increased HLTF and decreased miR-145 expression: this microRNA targets the 3 0 UTR of HLTF mRNA [86,87]. Interestingly, CHFR, the E3 ubiquitin ligase that targets HLTF for degradation at the proteasome also functions as a mitotic checkpoint.…”

“…However, in this model, no Hltf promoter hypermethylation was reported, suggesting a different pathway for Hltf silencing in mice or no association with AOM treatment. Sandhu et al [84] inactivated Hltf in mice by replacing exons 1-5 with a LacZ cDNA fused in frame with the endogenous Hltf coding sequence. These mice showed a normal development.…”

HLTF’s Ancient HIRAN Domain Binds 3′ DNA Ends to Drive Replication Fork Reversal

“…For instance, under conditions of nucleotide depletion, HLTF-mediated fork reversal could protect the fork by limiting ssDNA accumulation. Notably, HLTF is silenced in more than 40% of colon cancers, and its disruption promotes genome instability and intestinal carcinogenesis on the Apc min/+ mutant background in mice (Sandhu et al, 2012; Unk et al, 2010). The Cancer Genome Atlas (TCGA) also indicates that HLTF amplification is observed in many cancers.…”

HIV-1 Vpr degrades the HLTF DNA translocase in T cells and macrophages

“…By ensuring the completion of S-phase following DNA damage, Rad5/HLTF/SHPRH contribute to genome integrity. HLTF is a DNA-binding protein (39-41) first described as a transcription factor (42,43), but later authenticated as a protein involved in DNA repair, in tumor suppression, and in the early stages of carcinogenesis (44)(45)(46)(47). Although both HLTF and SHPRH are able to polyubiquitinate PCNA, they do not act redundantly (48).…”