RKO-E6

H₂O₂ Inhibits Fatty Acid Accumulation by Promoting FASN Ubiquitination and Degradation in P53^+/+ CRC Cells

Oxidative stress and altered lipid metabolism are two characteristics of cancer cells. Han et al. investigated the crosstalk between these two biological processes in CRC.

Oxidative stress agent H₂O₂ acutely reduced lipid droplets in p53 wild-type CRC cells (RKO), but not p53-null CRC cells (RKO E6). Lipid accumulation inhibition by H₂O₂ was compromised by p53 knockdown, suggesting that p53 mediates fatty acid accumulation suppression in CRC cells (Fig. 1A, B). Additionally, H₂O₂ treatment led to induction of p53 and inhibition of FASN protein expression without altering their mRNA levels in RKO cells (Fig. 1C, D). FASN repression by H₂O₂ was rescued by p53 knockdown (Fig. 1D). Proteasome inhibitor MG132 abrogated H₂O₂-mediated FASN repression (Fig. 1E). FASN protein is more stable in p53-null CRC cells compared with p53-wild-type CRC cells, and p53 knockdown suppressed FASN protein degradation (Fig. 1F, G). Furthermore, FASN expression inversely correlated with oxidative DNA damage marker 8-OxoG in p53 wild-type but not null CRC tissues (Fig. 1H). Finally, H₂O₂ increased FASN ubiquitination in a p53-dependent manner (Fig. 1I-K). Taken together, these findings reveal that FASN is destabilized by H₂O₂ via p53-dependent ubiquitination in CRC.