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

• 作者: Bo Yang Hong Jiang Ji Cao Kaixiong Ye Li Jiang Meidan Ying Meng Yuan Qiaojun He Xiaobing Chen Yitang Sun Zhongni Xia
• 来源期刊: 药学学报（英文版）
• 年，卷（期）: 2020,（8）
• 所属期刊栏目: Original articles
• 页码范围: 1426-1439
• 页数: 14页
• 语种: 英文

摘要

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 in vitro and in vivo.Of interest,CLDN3 undergoes S-palmitoylation on three juxtamembrane cysteine residues,which contribute to the accurate plasma membrane localization and protein stability of CLDN3.Moreover,the deprivation of S-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.Thus,our work reveals S-palmitoylation as a novel regulatory mechanism that modulates CLDN3 function,which implies that targeting ZDHHC12-mediated CLDN3 S-palmitoylation might be a potential strategy for ovarian cancer therapy.