FASN negatively regulates p65 expression by reducing its stability via Thr254 phosphorylation and isomerization by Pin1

Abstract

Fatty acid synthase (FASN), the sole cytosolic enzyme responsible for de novo palmitate synthesis in mammalian cells, has been associated with poor prognosis in cancer and shown to cause drug and radiation resistance by upregulating DNA-damage repair via suppression of p65 expression. Targeting FASN by repurposing proton pump inhibitors has generated impressive outcomes in triple negative breast cancer patients. While p65 regulation of DNA damage repair was thought to be due to its suppression of PARP1 gene transcription, the mechanism of FASN regulation of p65 expression was unknown. In this study, we show that FASN regulates p65 stability by regulating its phosphorylation at Thr²⁵⁴, which recruits the peptidyl-prolyl cis/trans isomerase Pin1 that is known to stabilize many proteins in nucleus. This regulation is mediated by palmitate, the FASN catalytic product, not by FASN protein per se. This finding of FASN regulation of p65 stability via phosphorylation of Thr²⁵⁴ and isomerization by Pin1 implicates that FASN and its catalytic product palmitate may play an important role in regulating protein stability in general and p65 more specifically.