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Helicase-like transcription factor (Hltf) gene-deletion promotes oxidative phosphorylation (OXPHOS) in colorectal tumors of AOM/DSS-treated mice.

ABSTRACT: The helicase-like transcription factor (HLTF) gene-a tumor suppressor in human colorectal cancer (CRC)-is regulated by alternative splicing and promoter hypermethylation. In this study, we used the AOM/DSS-induced mouse model to show Hltf-deletion caused poor survival concomitant with increased tumor multiplicity, and dramatically shifted the topographic distribution of lesions into the rectum. Differential isoform expression analysis revealed both the truncated isoform that lacks a DNA-repair domain and the full length isoform capable of DNA damage repair are present during adenocarcinoma formation in controls. iPathwayGuide identified 51 dynamically regulated genes of 10,967 total genes with measured expression. Oxidative Phosphorylation (Kegg: 00190), the top biological pathway perturbed by Hltf-deletion, resulted from increased transcription of Atp5e, Cox7c, Uqcr11, Ndufa4 and Ndufb6 genes, concomitant with increased endogenous levels of ATP (p = 0.0062). Upregulation of gene expression, as validated with qRT-PCR, accompanied a stable mtDNA/nDNA ratio. This is the first study to show Hltf-deletion in an inflammation-associated CRC model elevates mitochondrial bioenergetics.

SUBMITTER: Helmer RA

PROVIDER: S-EPMC6713344 | biostudies-literature | 2019

REPOSITORIES: biostudies-literature

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Helicase-like transcription factor (Hltf) gene-deletion promotes oxidative phosphorylation (OXPHOS) in colorectal tumors of AOM/DSS-treated mice.

Helmer Rebecca A RA Kaur Gurvinder G Smith Lisa A LA Chilton Beverly S BS

PloS one 20190828 8

The helicase-like transcription factor (HLTF) gene-a tumor suppressor in human colorectal cancer (CRC)-is regulated by alternative splicing and promoter hypermethylation. In this study, we used the AOM/DSS-induced mouse model to show Hltf-deletion caused poor survival concomitant with increased tumor multiplicity, and dramatically shifted the topographic distribution of lesions into the rectum. Differential isoform expression analysis revealed both the truncated isoform that lacks a DNA-repair d ...[more]

PMID: 31461471

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Project description:The helicase-like transcription factor (HLTF) gene – a tumor suppressor in human colorectal cancer (CRC) - is regulated by alternative splicing and promoter hypermethylation. The detection of hypermethylated HLTF DNA in fecal occult blood tests is an indicator of disease recurrence and poor survival. Hltf-deficiency in the ApcMin/+ mouse strain increased the formation of intestinal adenocarcinoma with a high incidence of gross chromosomal instabilities. To investigate Hltf-deletion effects in CRC without cross-breeding into a tumorigenic strain, Hltf-deletion was studied in mice treated with the carcinogen azoxymethane (AOM) and the proinflammatory agent dextran sulfate (DSS). Hltf-deletion resulted in weight loss beginning at treatment week 6, and poor survival (Kaplan-Meier survival plot). Hltf-deletion increased tumor multiplicity compared to controls, and dramatically shifted the topographic distribution of lesions into the rectum. Differential isoform expression analysis of lesions from control mice revealed both the truncated isoform that lacks a DNA-repair domain and the full length isoform capable of DNA damage repair are present (3:1.8 ratio) during adenocarcinoma formation. iPathwayGuide identified 51 dynamically regulated genes of 10,967 total genes with measured expression. Oxidative Phosphorylation (Kegg: 00190), the top biological pathway (p=0.006; p value correction: Bonferroni) perturbed by Hltf-deletion, resulted from increased transcription of Atp5e, Cox7c, Uqcr11, Ndufa4 and Ndufb6 genes, concomitant with increased endogenous levels of ATP (p=0.0176). Upregulation of gene expression, as validated with qRT-PCR, was accompanied by a stable mtDNA/nDNA ratio. This is the first study to show Hltf-deletion in an inflammation-associated CRC model elevates mitochondrial bioenergetics. The distal shift in tumorigenesis indicates the detection of hypermethylated HLTF DNA in human stool samples might be a prognostic biomarker for distal (left-sided) colorectal cancer rather than proximal (right-sided) colon cancer.

Project description:BackgroundThe primary energy-producing pathway in eukaryotic cells, the oxidative phosphorylation (OXPHOS) system, comprises proteins encoded by both mitochondrial and nuclear genes. To maintain the function of the OXPHOS system, the pattern of substitutions in mitochondrial and nuclear genes may not be completely independent. It has been suggested that slightly deleterious substitutions in mitochondrial genes are compensated by substitutions in the interacting nuclear genes due to positive selection. Among the four largest insect orders, Coleoptera (beetles), Hymenoptera (sawflies, wasps, ants, and bees), Diptera (midges, mosquitoes, and flies) and Lepidoptera (moths and butterflies), the mitochondrial genes of Hymenoptera exhibit an exceptionally high amino acid substitution rate while the evolution of nuclear OXPHOS genes is largely unknown. Therefore, Hymenoptera is an excellent model group for testing the hypothesis of positive selection driving the substitution rate of nuclear OXPHOS genes. In this study, we report the evolutionary rate of OXPHOS genes in Hymenoptera and test for evidence of positive selection in nuclear OXPHOS genes of Hymenoptera.ResultsOur analyses revealed that the amino acid substitution rate of mitochondrial and nuclear OXPHOS genes in Hymenoptera is higher than that in other studied insect orders. In contrast, the amino acid substitution rate of non-OXPHOS genes in Hymenoptera is lower than the rate in other insect orders. Overall, we found the dN/dS ratio of the nuclear OXPHOS genes to be higher in Hymenoptera than in other insect orders. However, nuclear OXPHOS genes with high dN/dS ratio did not always exhibit a high amino acid substitution rate. Using branch-site and site model tests, we identified various codon sites that evolved under positive selection in nuclear OXPHOS genes.ConclusionsOur results showed that nuclear OXPHOS genes in Hymenoptera are evolving faster than the genes in other three insect orders. The branch test suggested that while some nuclear OXPHOS genes in Hymenoptera show a signature of positive selection, the pattern is not consistent across all nuclear OXPHOS genes. As only few codon sites were under positive selection, we suggested that positive selection might not be the only factor contributing to the rapid evolution of nuclear OXPHOS genes in Hymenoptera.

Dataset Information

Helicase-like transcription factor (Hltf) gene-deletion promotes oxidative phosphorylation (OXPHOS) in colorectal tumors of AOM/DSS-treated mice.

Publications

Helicase-like transcription factor (Hltf) gene-deletion promotes oxidative phosphorylation (OXPHOS) in colorectal tumors of AOM/DSS-treated mice.

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