PRDX6 Prevents NNMT Ubiquitination and Degradation as a Nonenzymatic Mechanism to Promote Ovarian Cancer Progression

Abstract Cancer cells cope with oxidative stress for their proliferation and metastasis by equipping antioxidant systems, among which the antioxidant enzymes peroxiredoxins (PRDXs) play crucial roles. However, whether PRDXs exhibit nonenzymatic functions remains unclear. Here, it is shown that the 1‐cysteine PRDX (PRDX6) upregulates nicotinamide N‐methyltransferase (NNMT) to promote the growth and metastasis of ovarian cancer cells, independently of PRDX6's enzymatic activities. Mechanistically, PRDX6 interacts with NNMT to prevent its binding to the E3 ubiquitin ligase tripartite‐motif protein 56 (TRIM56), leading to the inhibition of NNMT ubiquitination at lysine 23 and 210 and suppression of subsequent proteasomal degradation. In addition, PRDX6‐mediated NNMT upregulation activates mitogen‐activated protein kinase (MAPK) signaling, thereby promoting the growth and metastasis of ovarian cancer cells. Notably, PRDX6 overexpression is associated with higher NNMT protein levels in human ovarian cancer tissues and is predictive of poor prognosis of ovarian cancer patients. Overall, the findings illustrate a critical oncogenic mechanism of the antioxidant enzyme PRDX6 in promoting ovarian cancer progression beyond its enzymatic mechanisms.