ZDHHC12-mediated claudin-3 S-palmitoylation determines ovarian cancer progression

Abstract

The membrane protein claudin-3 (CLDN3) is critical for the formation and maintenance of tight junction and its high expression has been implicated in dictating malignant progression in various cancers. However, the post-translational modification of CLDN3 and its biological function remains poorly understood. Here, we report that CLDN3 is positively correlated with ovarian cancer progression both <i>in vitro</i> and <i>in vivo.</i> Of interest, CLDN3 undergoes <i>S</i>-palmitoylation on three juxtamembrane cysteine residues, which contribute to the accurate plasma membrane localization and protein stability of CLDN3<i>.</i> Moreover, the deprivation of <i>S</i>-palmitoylation in CLDN3 significantly abolishes its tumorigenic promotion effect in ovarian cancer cells. By utilizing the co-immunoprecipitation assay, we further identify ZDHHC12 as a CLDN3-targating palmitoyltransferase from 23 ZDHHC family proteins. Furthermore, the knockdown of ZDHHC12 also significantly inhibits CLDN3 accurate membrane localization, protein stability and ovarian cancer cells tumorigenesis<i>.</i> Thus, our work reveals <i>S</i>-palmitoylation as a novel regulatory mechanism that modulates CLDN3 function, which implies that targeting ZDHHC12-mediated CLDN3 <i>S</i>-palmitoylation might be a potential strategy for ovarian cancer therapy.