Abstract
Peroxisome proliferator-activated receptor alpha (PPARA) is the molecular target of fibrates commonly used to treat dyslipidemia and diabetes. Recently, the potential role of PPARA in other pathological conditions, such as cancers, has been recognized. Here, using bioinformatics analysis, we found that PPARA was expressed at relatively low levels in pancancers, and Kaplan-Meier analyses revealed that high PPARA protein expression was correlated with better survival of patients with colon cancer. In vitro experiments showed that fenofibrate regulated cell cycle distribution, promoted apoptosis, and suppressed cell proliferation and epithelial mesenchymal transition by activating PPARA. PPARA activation inhibited DNMT1 activity and abolished methylation-mediated CDKN2A repression. Downregulation of cyclin-CDK complexes led to the restoration of CDKN2A, which caused cell cycle arrest in the G1 phase via regulation of the CDKN2A/RB/E2F pathway. Finally, we demonstrated that fenofibrate administration inhibited tumor growth and DNMT1 activity in vivo. The PPARA agonist, fenofibrate, might serve as an applicable agent for epigenetic therapy of colon cancer patients.
Highlights
Colorectal cancer (CRC) ranks third in terms of morbidity and fourth in terms of mortality
We demonstrated that the Peroxisome proliferator-activated receptor alpha (PPARA) agonist, fenofibrate, inhibited DNA methyltransferase 1 (DNMT1)-mediated methylation of CDKN2A and exerted anticancer effects by promoting cell apoptosis, inhibiting cell migration, and suppressing cell proliferation via the CDKN2A/RB/E2F pathway
We focused on the clinical significance of PPARA expression
Summary
Colorectal cancer (CRC) ranks third in terms of morbidity and fourth in terms of mortality. CRC is the most common type of cancer worldwide, with almost 900,000 deaths each year [1, 2]. New treatment options, including immunotherapy and neoadjuvant chemotherapy, have significantly improved patient prognosis, the 5-year survival rate of CRC remains below 15% [3]. CpG islands (CGI) are contiguous groups of dinucleotides mainly located at the 5′ end of a gene and are characterized by high GC content [4]. Most CGIs in gene promoters are unmethylated, allowing active transcription [5]. CGI methylation changes are hallmarks of many human cancers and lead to concomitant gene inactivation [6,7,8]. DNMT3a and DNMT3b mainly act as de novo methyltransferases [10]
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