PPARα regulates tumor cell proliferation and senescence via a novel target gene carnitine palmitoyltransferase 1C

Carnitine palmitoyltransferase 1C (CPT1C), an enzyme located in the outer mitochondria membrane, has a crucial role in fatty acid transport and oxidation. It is also involved in cell proliferation and is a potential driver for cancer cell senescence. However, its upstream regulatory mechanism is unknown. Peroxisome proliferator activated receptor alpha (PPAR alpha) is a ligand-activated transcription factor that regulates lipid metabolism and tumor progression. The current study aimed to elucidate whether and how PPAR alpha regulates CPT1C and then affects cancer cell proliferation and senescence. Here, for the first time we report that PPAR alpha directly activated CPT1C transcription and CPT1C was a novel target gene of PPAR alpha, as revealed by dual-luciferase reporter and chromatin immunoprecipitation (ChIP) assays. Moreover, regulation of CPT1C by PPAR alpha was p53-independent. We further confirmed that depletion of PPAR alpha resulted in low CPT1C expression and then inhibited proliferation and induced senescence of MDA-MB-231 and PANC-1 tumor cell lines in a CPT1C-dependent manner, while forced PPAR alpha overexpression promoted cell proliferation and reversed cellular senescence. Taken together, these results indicate that CPT1C is a novel PPAR alpha target gene that regulates cancer cell proliferation and senescence. The PPAR alpha-CPT1C axis may be a new target for the intervention of cancer cellular proliferation and senescence.