Abstract
Background: The activation of peroxisome proliferator-activated receptor alpha (PPARα) has been shown to reprogram tumor metabolism and exhibits great potential for treating anti-oral tumorigenesis.Methods: In this study, we used a pathway-based strategy to explore possible functional pathways involved in the anticancer activity of PPARα in oral cancer cells through next-generation sequencing (NGS) and bioinformatic approaches.Results: We found that 3919 genes were upregulated and 1060 genes were downregulated through PPARα activation. These genes were mainly involved in the proteasomal, mRNA surveillance, spliceosomal, RNA transport, and RNA degradation pathways, as indicated by GO and KEGG enrichment analysis. Importantly, a total of 13 upregulated genes in the RNA degradation pathway were identified including 3 core exosome factor genes (RRP43, RRP42, and CSL4), 2 TRAMP complex genes (TRF4 and Mtr4), 2 exosome cofactor genes (RRP6 and MPP6), 2 CCR4-NOT complex genes (CNOT2 and CNOT3), 2 Ski complex genes (SKI2 and Ski3), 1 decapping complex gene (EDC4), and 1 gene involved in 5’ exoribonuclease activity (XRN1).Conclusion: Our findings suggest that the activation of PPARα to upregulate the RNA degradation pathway might provide a new strategy for oral cancer treatment.
Highlights
The diagnosis of oral cancer at an early stage provides an approximately 80% survival rate, while diagnosis at a late stage decreases the survival rate to 20% [1, 2]
Our findings suggest that the activation of PPARα to upregulate the RNA degradation pathway might provide a new strategy for oral cancer treatment
Our previous studies showed that the activation of PPARα through fenofibrate was involved in several anti-oral cancer activities in both animal and cell culture models including (a) the suppression of the development of the preneoplastic lesion into oral squamous cell carcinoma [8], (b) the downregulation of mTOR activity by TSC1/2-dependent signaling through the stimulation of AMPK and the repression of Akt [9, 10], (c) the regulation of the expression of genes related to mitochondrial energy metabolism [6], and (d) the inhibition of oral cancer cell proliferation and the induction of metabolic reprogramming by switching the energy production way from the Warburg effect to mitochondrial oxidative phosphorylation [11]
Summary
The diagnosis of oral cancer at an early stage provides an approximately 80% survival rate, while diagnosis at a late stage decreases the survival rate to 20% [1, 2]. Our previous studies showed that the activation of PPARα through fenofibrate was involved in several anti-oral cancer activities in both animal and cell culture models including (a) the suppression of the development of the preneoplastic lesion into oral squamous cell carcinoma [8], (b) the downregulation of mTOR activity by TSC1/2-dependent signaling through the stimulation of AMPK and the repression of Akt [9, 10], (c) the regulation of the expression of genes related to mitochondrial energy metabolism [6], and (d) the inhibition of oral cancer cell proliferation and the induction of metabolic reprogramming by switching the energy production way from the Warburg effect to mitochondrial oxidative phosphorylation [11]. In PPARαmediated anti-oral tumorigenesis, it is possible that some oncogenic pathways or alterations have yet to be described
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