![]() ![]() ![]() Importantly, the cellular phenotypes associated with ALDH7A1-depletion, increased migration and invasiveness, were corrected by restoring PPAR activity. Analysis of cancer RNAseq data from TCGA showed that low ALDH7A1 mRNA levels correlate with a low PPAR activity signature, and with poor survival prognosis in patients with hepatocellular carcinoma and renal clear cell carcinoma. Metabolic profiling showed that ALDH7A1-depletion reduced the levels of metabolites that serve as activating ligands for PPARs. Metabolite-regulated control of PPAR activity contributes to cellular homeostasis through feedback regulation on the expression on enzymes involved in glucose, amino acid and lipid metabolism. PPARs (Peroxisome proliferator-activated receptors) are ligand-activated transcription factors, regulated by cellular metabolites. In this study, we provide evidence for a role of ALDH isoform 7A1 (ALDH7A1) in human cancer, and link this to regulation of PPAR activity. Evidence of the roles of other ALDH isoforms in cancer remains equivocal. Cells with high ALDH1 activity have been linked to poor outcome in some cancers, albeit not in others. Notably, ALDH1 is thought to be oncogenic in breast cancer. The human ALDH family comprises 19 enzymes that catalyze NAD(P)+ dependent oxidation of aldehydes to their corresponding carboxylic acids and NAD(P)H. Changes in metabolite levels can affect expression profiles, epigenetic marks and chromatin organization in cancer, with resulting changes in cellular phenotypes, metastatic potential, as well as on the tumor microenvironment. Mutations and/or altered expression of metabolic enzymes such as succinate dehydrogenase, pyruvate kinase and isocitrate dehydrogenase are linked to tumor initiation, development and drug resistance. In addition to the well-known shift of cancer cells to aerobic glycolysis, mutations or changes in the expression of metabolic enzymes have been identified as potential cancer drivers. We provide evidence that low ALDH7A1 expression is a useful prognostic marker of poor clinical outcome for hepatocellular and renal clear cell carcinomas and hypothesize that patients with low ALDH7A1 might benefit from therapeutic approaches addressing PPARα activity.Ī growing body of evidence links changes in metabolism to cancer. Low ALDH7A1 protein levels correlated with poor clinical outcome in hepatocellular and renal clear cell carcinoma patients. Treatment with a PPARα agonist restored normal cellular behavior. ALDH7A1-depletion led to reduced PPAR transcriptional activity. Metabolic profiling showed that endogenous PPARα ligands were reduced in ALDH7A1-depleted cells. Using pathway and gene set enrichment analysis, we establish a correlation between low ALDH7A1 levels, reduced PPAR signaling and reduced patient survival. Analysis of publically available cancer gene expression data revealed that ALDH7A1 mRNA levels were reduced in many human cancers, and that this correlated with poor survival in kidney and liver cancer patients. Depletion of ALDH7A1 led to reduced levels of metabolites identified as ligands for Peroxisome proliferator-activated receptor (PPARα). Resultsĭepletion of ALDH7A1 increased cellular migration and invasiveness in vitro. Immunohistochemistry was used to assess ALDH7A1 expression in tissue samples from cancer patients. A variety of statistical tests used to evaluate these analyses are described in detail in the methods section. Computational pathway and gene set enrichment analysis was used to identify signaling pathways and cellular processes that were correlated with reduced ALDH7A1 expression in cancer. Publically available cancer gene expression data was interrogated to identify a gene-expression signature associated with depletion of ALDH7A1. 1H-NMR metabolite profiling was used to identify metabolic changes in ALDH7A1-depleted cells. The role of the human ortholog was examined using RNA interference in cell-based assays of cell migration and invasion. MethodsĪLDH7A1 was identified as a potential cancer gene using a Drosophila in vivo metastasis model. Here, we explore the mechanism by which metabolic changes dependent on aldehyde dehydrogenase impact cancer development. #INMR ACRONYM DRIVERS#Changes in cellular metabolism are now recognized as potential drivers of cancer development, rather than as secondary consequences of disease. ![]()
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