Metabolic control of PPAR activity by aldehyde dehydrogenase regulates invasive cell behavior and predicts survival in hepatocellular and renal clear cell carcinoma

Abstract

BackgroundChanges in cellular metabolism are now recognized as potential drivers of cancer development, rather than as secondary consequences of disease. Here, we explore the mechanism by which metabolic changes dependent on aldehyde dehydrogenase impact cancer development.MethodsALDH7A1 was identified as a potential cancer gene using a Drosophila in vivo metastasis model. The role of the human ortholog was examined using RNA interference in cell-based assays of cell migration and invasion. 1H-NMR metabolite profiling was used to identify metabolic changes in ALDH7A1-depleted cells. Publically available cancer gene expression data was interrogated to identify a gene-expression signature associated with depletion of ALDH7A1. 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. A variety of statistical tests used to evaluate these analyses are described in detail in the methods section. Immunohistochemistry was used to assess ALDH7A1 expression in tissue samples from cancer patients.ResultsDepletion of ALDH7A1 increased cellular migration and invasiveness in vitro. Depletion of ALDH7A1 led to reduced levels of metabolites identified as ligands for Peroxisome proliferator-activated receptor (PPARα). 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. Using pathway and gene set enrichment analysis, we establish a correlation between low ALDH7A1 levels, reduced PPAR signaling and reduced patient survival. Metabolic profiling showed that endogenous PPARα ligands were reduced in ALDH7A1-depleted cells. ALDH7A1-depletion led to reduced PPAR transcriptional activity. Treatment with a PPARα agonist restored normal cellular behavior. Low ALDH7A1 protein levels correlated with poor clinical outcome in hepatocellular and renal clear cell carcinoma patients.ConclusionsWe 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.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5061-7) contains supplementary material, which is available to authorized users.

Peroxisome proliferator‐activated receptor activity correlates with poor survival in patients resected for hepatocellular carcinoma

“…A recent study used publicly available RNA sequencing data from The Cancer Genome Atlas (TCGA) to investigate correlations between expression of the Aldehyde Dehydrogenase (ALDH) isoform ALDH7A1, PPAR activity and survival in patients with HCC and kidney cancer. Hierarchical clustering of RNA levels from HCC tumors showed that patients with low PPAR activity had significantly reduced overall survival 15 . Augmentation of PPARα activity, but not of the other PPAR isoforms, resulted in suppression of cancer‐indicative phenotypes in culture.…”

“…In addition, ALDHs have been linked to poor outcome in some cancers 16,17 . Low ALDH7A1 mRNA levels correlated with a low PPAR activity signature, and ALDH7A1 depletion reduced levels of metabolites that serve as activating ligands for PPARs 15 . In addition, a recent study in 804 patients showed a correlation between low PPARα expression, evaluated with immunohistochemistry, and shorter survival 18 .…”

A panel of eight mRNA signatures improves prognosis prediction of osteosarcoma patients

“…PPARs (Peroxisome proliferator-activated receptors) are ligand-activated transcription factors that are crucial regulators of glucose and lipid metabolism, cellular homeostasis, and inflammation. [ 41 , 42 ] Moreover, cellular growth and differentiation are key processes for carcinoma development and progression. The findings in our study are consistent with recently reported results, [ 43 ] which show that neuroactive ligand-receptor interaction and the PPAR signaling pathway are highly associated with osteosarcoma.…”

Genome-Wide Screen for Context-Dependent Tumor Suppressors Identified Using in Vivo Models for Neoplasia in Drosophila

“…In addition to finding genes linked to known growth control pathways, a number of novel connections to Yki and EGFR driven tissue growth have been identified, which merit further investigation in the Drosophila genetic model. Exploring the potential relevance of genes identified in this manner to human cancer will involve assessing the correlation of candidate gene expression with clinical outcome across a broad range of cancers (e.g., (Andrejeva et al 2018;Eichenlaub et al 2018)), as a starting point to identify biomarkers as well as novel candidate drug targets.…”