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.
Highlights
Given the increasing changes in attitude toward the risks of exposure to cigarette smoking and increasing air pollution, the prevalence of lung squamous cell carcinoma cases has declined; lung adenocarcinoma (LUAD) became the most common lung cancer in 1998–2002 (Lortet-Tieulent et al, 2014; Travis et al, 2015)
We found that high expression of ZDHHC5 and ZDHHC15 was associated with an unfavorable prognosis and a favorable outcome, respectively
This study identified ZDHHC5 as a key protein acyltransferase (PATs) in LUAD for its over-expression and malignant prognosis in LUAD patients, overturning its previously refuted prognostic value
Summary
Given the increasing changes in attitude toward the risks of exposure to cigarette smoking and increasing air pollution, the prevalence of lung squamous cell carcinoma cases has declined; lung adenocarcinoma (LUAD) became the most common lung cancer in 1998–2002 (Lortet-Tieulent et al, 2014; Travis et al, 2015). Despite the emerging improvements in chemoradiotherapy, targeted therapy, and immunotherapy, the 5-year survival rates remain low (7–20%), and recurrence rates remain high at 30–50% (Miyata et al, 2015). Cancer stemness properties, including self-renewal and differentiation, was initially attributed to normal stem cells (Malta et al, 2018). Recent advances in high-throughput technology and machine learning have improve novel understanding of tumor heterogeneity and developed transcriptional classifications of LUAD, including molecular subtypes (Ruiz-Cordero and Devine, 2020; Wadowska et al, 2020) and immune classification (Thorsson et al, 2018). Malta et al (2018) used an innovative one-class logistic regression machine-learning algorithm (OCLR) to analyze the molecular profiles of normal stem cell types, and they applied the OCLRbased signatures to The Cancer Genome Atlas (TCGA) datasets to obtain mRNA stemness indices (mRNAsi). We characterized the expression of LUAD stem cell genes by mRNAsi and weighted gene co-expression network analysis (WGCNA) was used to construct a LUAD stem cell gene network (Zhang et al, 2020)
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