APT1-mediated depalmitoylation of CLDN7 promotes clear cell renal cell carcinoma progression via ubiquitin-proteasomal degradation and epithelial-mesenchymal transition

Claudin-7 (CLDN7) is a tight junction protein whose expression is frequently down-regulated in clear cell renal cell carcinoma (ccRCC) and is correlated with disease progression; however, the underlying regulatory mechanism remains unclear. Here, we demonstrate that CLDN7 undergoes S-palmitoylation at Cys184 and Cys186 and that loss of this modification destabilizes CLDN7 by enhancing its ubiquitination and proteasomal degradation, which is accompanied by aberrant subcellular localization and reduced inhibitory effects on tumor cell migration, invasion, and lung colonization in vitro and in vivo . Mechanistically, we identified acyl-protein thioesterase 1 (APT1) as a key regulator that catalyzes CLDN7 depalmitoylation, interacts with CLDN7, and mediates its mislocalization and degradation. APT1 is highly expressed in human ccRCC tissues, and its knockdown stabilizes CLDN7 and suppresses invasive phenotypes, whereas APT1 overexpression partially counteracts the tumor-suppressive effects of CLDN7. Collectively, these findings delineate a posttranslational APT1-CLDN7 regulatory axis that drives CLDN7 degradation and ccRCC aggressiveness and highlight APT1 inhibition as a potential therapeutic strategy for metastatic ccRCC.