Potential Role of S-Palmitoylation in Cancer Stem Cells of Lung Adenocarcinoma

Abstract

S-palmitoylation, catalyzed by a family of 23 zinc finger Asp-His-His-Cys (DHHC) domain-containing (ZDHHC) protein acyltransferases localized on the cell membrane. However, stemness genes modulated by ZDHHCs in lung adenocarcinoma (LUAD) remain to be defined. Previously, we have constructed a network of cancer stem cell genes, including INCENP, based on mRNA stemness indices (mRNAsi) of LUAD. INCENP has the function of a chromosomal passenger complex locating to centromeres, which is performed by the conserved region of its N-terminal domain. INCENP protein with a deletion of the first non-conserved 26 amino acid sequence failed to target centromeres. However, the exact function of the deleted sequence has not been elucidated. To identify novel cancer stem cell-relevant palmitoylated proteins and responsible ZDHHC enzymes in LUAD, we analyzed multi-omics data obtained from the database of The Cancer Genome Atlas (TCGA), Gene Expression Omnibus (GEO), Clinical Proteomic Tumor Analysis Consortium (CPTAC), and the Human Protein Atlas (HPA). ZDHHC5 is distinguished from the ZDHHC family for being up-regulated in mRNA and protein levels and associated with malignant prognosis. ZDHHC5 was positively associated with INCENP, and the correlation score increased with LUAD stages. CSS-Palm results showed Cys15 was the S-palmitoylation site of INCENP. Interestingly, Cys15 locates in the 1–26 aa sequence of INCENP, and is a conserved site across species. As INCENP is a nuclear protein, we predicted that the nuclear localization signal of ZDHHC5 was specific to the importin αβ pathway, and the result of immunofluorescence proves that ZDHHC5 is located in the nucleoplasm, in addition to the plasma membrane. Therefore, our study indicates the S-palmitoylation of INCENP mediated by ZDHHC5 as a potential mechanism of S-palmitoylation to modulate CSCs in LUAD.

ZDHHC11B is decreased in lung adenocarcinoma and inhibits tumorigenesis via regulating epithelial–mesenchymal transition

“…It was found that ZDHHC5, ZDHHC17, ZDHHC18, and ZDHHC23 promote cellular self-renewal by targeting glioma stem cells, which in turn induces malignant progression of tumor cells. [26][27][28] We constructed a stable overexpression cell model and conducted functional experiments that identified inhibitory factors for tumor cell growth associated with a high expression of ZDHHC11B. We then conducted tumorigenic experiments in mice that confirmed these results.…”

“…Our study revealed that ZDHHC11B could be a protective factor for LUAD and its low expression was negatively correlated with the prognosis of patients with LUAD. It was found that ZDHHC5, ZDHHC17, ZDHHC18, and ZDHHC23 promote cellular self‐renewal by targeting glioma stem cells, which in turn induces malignant progression of tumor cells 26–28 . We constructed a stable overexpression cell model and conducted functional experiments that identified inhibitory factors for tumor cell growth associated with a high expression of ZDHHC11B.…”

Hypomethylation-induced prognostic marker zinc finger DHHC-type palmitoyltransferase 12 contributes to glioblastoma progression

“…The role of the ZDHHC family in cancer has been widely reported. For example, ZDHHC5 has been found to regulate cancer stem cells and associated with malignant prognosis in lung adenocarcinoma (38), ZDHHC9 has been found to induce and stabilize PD-L1 protein, then drive cancer cells from immune surveillance in breast cancer (39), and the melanocortin-1 receptor palmitoylated by ZDHHC13 has been found to promote pigmentation and protect against melanoma (17).…”

Post-Translational Modifications by Lipid Metabolites during the DNA Damage Response and Their Role in Cancer

“…However, the majority of protein palmitoylation is catalyzed by the PAT family, which contains zinc finger structures (ZDHHCs). PAT and APT enzyme function is known to be associated with cancer, and the regulation of these enzymes has been suggested as a potential target for cancer treatment [ 162 , 163 , 164 ].…”