Acetylation-dependent USP7-TRIM25 axis drives oncogenic progression in non-small cell lung cancer

Tripartite motif containing 25 (TRIM25), an E3 ubiquitin ligase that plays an important role in bioprocesses, is frequently elevated in malignant tumors. However, it remains unclear how TRIM25 protein expression is regulated in non-small cell lung cancer (NSCLC). Here, we find that TRIM25 is hyper-expressed in NSCLC tissues and associated with poor prognosis of NSCLC patients. Both in vitro and in vivo experiments indicate that TRIM25 facilitates tumor proliferation and metastasis. Mechanistically, acetylation is identified as a critical post-translational modification (PTM) regulating TRIM25 protein stability in NSCLC. The lysine acetyltransferase cAMP-responsive element-binding (CREB)-binding protein (CBP) mediates acetylation of TRIM25 at lysine 392, which is counteracted by the deacetylase Sirtuin 7 (SIRT7). Notably, the acetylation of TRIM25 enhances its interaction with ubiquitin specific peptidase 7 (USP7), resulting in reduced ubiquitination of TRIM25. In summary, our study reveals a novel acetylation modification site, thus providing new insights into an epigenetic regulation of TRIM25 in human cancer, and suggesting that pharmacological inhibition of TRIM25 acetylation is a potential anti-tumor strategy.