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Fenofibrate Exerts Antitumor Effects in Colon Cancer via Regulation of DNMT1 and CDKN2A

Rui Kong1, Nan Wang1, Wei Han1

  • 1Department of Gastroenterology, Shanghai Tenth People's Hospital Affiliated to Tongji University, Tongji University, School of Medicine, Shanghai 200072, China.

PPAR Research
|May 7, 2021
PubMed

Insights

Peroxisome proliferator-activated receptor alpha (PPARA) activation by fenofibrate inhibits colon cancer growth. This PPARA activation suppresses tumor cell proliferation and enhances patient survival, suggesting fenofibrate as a potential epigenetic therapy.

Area of Science:

  • Oncology
  • Molecular Biology
  • Pharmacology

Background:

  • Peroxisome proliferator-activated receptor alpha (PPARA) is a target of fibrates used for dyslipidemia and diabetes.
  • Emerging evidence suggests PPARA's involvement in various cancers.
  • PPARA expression is often low in many cancer types.

Purpose of the Study:

  • To investigate the role of PPARA in colon cancer.
  • To evaluate the therapeutic potential of PPARA activation using fenofibrate.
  • To elucidate the molecular mechanisms underlying PPARA's effect on colon cancer.

Main Methods:

  • Bioinformatics analysis of PPARA expression in pan-cancer datasets.
  • Kaplan-Meier survival analysis for colon cancer patients.
  • In vitro studies on cell cycle, apoptosis, proliferation, and epithelial-mesenchymal transition.
  • In vivo studies assessing tumor growth and DNMT1 activity.

Main Results:

  • Low PPARA expression observed in most cancers; high PPARA protein correlated with better survival in colon cancer patients.
  • Fenofibrate activated PPARA, leading to cell cycle arrest, apoptosis promotion, and suppressed proliferation and EMT in vitro.
  • PPARA activation inhibited DNMT1, restored CDKN2A expression, and induced G1 cell cycle arrest via the CDKN2A/RB/E2F pathway.
  • Fenofibrate administration inhibited tumor growth and DNMT1 activity in vivo.

Conclusions:

  • PPARA activation by fenofibrate demonstrates anti-cancer effects in colon cancer.
  • Fenofibrate modulates epigenetic mechanisms, including DNMT1 inhibition and CDKN2A restoration.
  • Fenofibrate holds promise as an epigenetic therapeutic agent for colon cancer.

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