ZDHHC9-mediated Bip/GRP78 S-palmitoylation inhibits unfolded protein response and promotes bladder cancer progression

Weiquan Li; Jingchong Liu; Tiexi Yu; Feiyi Lu; Qi Miao; Xiangui Meng; Wen Xiao; Hongmei Yang; Xiaoping Zhang

doi:10.1016/j.canlet.2024.217118

ZDHHC9-mediated Bip/GRP78 S-palmitoylation inhibits unfolded protein response and promotes bladder cancer progression

Cancer Lett. 2024 Aug 28:598:217118. doi: 10.1016/j.canlet.2024.217118. Epub 2024 Jul 18.

Authors

Weiquan Li¹, Jingchong Liu¹, Tiexi Yu¹, Feiyi Lu¹, Qi Miao¹, Xiangui Meng², Wen Xiao³, Hongmei Yang⁴, Xiaoping Zhang⁵

Affiliations

¹ Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, China.
² Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, China. Electronic address: mengxg@hust.edu.cn.
³ Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, China. Electronic address: wxuro20@hust.edu.cn.
⁴ Department of Pathogenic Biology, School of Basic Medicine, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430030, China. Electronic address: hyang@hust.edu.cn.
⁵ Department of Urology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, 430022, China; Shenzhen Huazhong University of Science and Technology Research Institute, Shenzhen, 518000, China. Electronic address: xzhang@hust.edu.cn.

PMID: 39002690
DOI: 10.1016/j.canlet.2024.217118

Abstract

Recent studies have highlighted palmitoylation, a novel protein post-translational modification, as a key player in various signaling pathways that contribute to tumorigenesis and drug resistance. Despite this, its role in bladder cancer (BCa) development remains inadequately understood. In this study, ZDHHC9 emerged as a significantly upregulated oncogene in BCa. Functionally, ZDHHC9 knockdown markedly inhibited tumor proliferation, promoted tumor cell apoptosis, and enhanced the efficacy of gemcitabine (GEM) and cisplatin (CDDP). Mechanistically, SP1 was found to transcriptionally activate ZDHHC9 expression. ZDHHC9 subsequently bound to and palmitoylated the Bip protein at cysteine 420 (Cys420), thereby inhibiting the unfolded protein response (UPR). This palmitoylation at Cys420 enhanced Bip's protein stability and preserved its localization within the endoplasmic reticulum (ER). ZDHHC9 might become a novel therapeutic target for BCa and could also contribute to combination therapy with GEM and CDDP.

Keywords: Bladder cancer; Palmitoylation; Unfolded protein response; ZDHHC9.

MeSH terms

Acyltransferases* / genetics
Animals
Apoptosis* / drug effects
Cell Line, Tumor
Cell Proliferation* / drug effects
Cisplatin / pharmacology
Deoxycytidine / analogs & derivatives
Deoxycytidine / pharmacology
Disease Progression
Endoplasmic Reticulum Chaperone BiP* / metabolism
Gemcitabine
Gene Expression Regulation, Neoplastic / drug effects
Heat-Shock Proteins / genetics
Heat-Shock Proteins / metabolism
Humans
Lipoylation*
Male
Mice
Mice, Nude
Unfolded Protein Response* / drug effects
Urinary Bladder Neoplasms* / drug therapy
Urinary Bladder Neoplasms* / genetics
Urinary Bladder Neoplasms* / metabolism
Urinary Bladder Neoplasms* / pathology
Xenograft Model Antitumor Assays

Substances

Acyltransferases
Endoplasmic Reticulum Chaperone BiP
HSPA5 protein, human
ZDHHC9 protein, human
Cisplatin
Heat-Shock Proteins
Deoxycytidine
Hspa5 protein, mouse
Gemcitabine