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Involvement of ZDHHC9 in lung adenocarcinoma: regulation of PD-L1 stability via palmitoylation

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Abstract

Palmitoylation is a post-translational modification occurring on cysteine residues, which process is catalyzed by a family of zinc finger Asp-His-His-Cys (DHHC) domain-containing (ZDHHC) protein acyltransferases. As a family member, ZDHHC9 plays a crucial role in varied malignancies by regulating protein stability via protein substrate palmitoylation. Based on the bioinformatic analysis of GEO gene microarray GSE75037 (|log2 fold change|> 1, P < 0.05), ZDHHC9 was defined as a significantly upregulated gene in lung adenocarcinoma (LUAD), which was also confirmed in our collected clinical specimens. It is necessary to explore the biological function of ZDHHC9 in LUAD cells. The follow-up functional experiments revealed that ZDHHC9 deficiency inhibited proliferation, migration, and invasion, while stimulated apoptosis in HCC827 cells. Besides, these malignant phenotypes could be accelerated by ZDHHC9 overexpression in A549. Moreover, we revealed that ZDHHC9 knockdown could promote PD-L1 protein degradation by reducing its palmitoylation level. The reduction of PD-L1 protein level could enhance anti-tumor immunity and inhibit the growth of LUAD cells. Therefore, our study uncovers the tumor-promoting role of ZDHHC9 in LUAD via regulating PD-L1 stability through palmitoylation, highlighting ZDHHC9 as a novel therapeutic target for LUAD.

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Authors and Affiliations

  1. Department of Oncology, Hebei Medical University, No. 361, Zhongshan East Road, Shijiazhuang, Hebei Province, China

    Zhe Li & Da Jiang

  2. The First Department of Medical Oncology, Cangzhou Central Hospital, Cangzhou, Hebei Province, China

    Zhe Li

  3. Department of Medical Oncology, the Fourth Hospital of Hebei Medical University, No. 12, Jiankang Road, Shijiazhuang, Hebei Province, China

    Da Jiang, Fengling Liu & Ying Li

Authors
  1. Zhe Li
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  2. Da Jiang
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  3. Fengling Liu
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  4. Ying Li
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Correspondence to Da Jiang.

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Supplementary Information

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11626_2023_755_MOESM1_ESM.docx

Supplementary file1 Figure S1. Efficiency detection of ZDHHC9 overexpressing or silencing. The expression of ZDHHC9 in A549 cells (A) and HCC827 cells (B) was detected by real-time PCR. (C) The protein levels of ZDHHC9 were tested by western blot. Data were assayed in triplicate and analyzed by one-way ANOVA followed by Tukey’s multiple comparison tests. ***P < 0.001. (DOCX 226 KB)

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Li, Z., Jiang, D., Liu, F. et al. Involvement of ZDHHC9 in lung adenocarcinoma: regulation of PD-L1 stability via palmitoylation. In Vitro Cell.Dev.Biol.-Animal 59, 193–203 (2023). https://doi.org/10.1007/s11626-023-00755-5

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  • DOI: https://doi.org/10.1007/s11626-023-00755-5

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