GSK3β palmitoylation mediated by ZDHHC4 promotes tumorigenicity of glioblastoma stem cells in temozolomide-resistant glioblastoma through the EZH2–STAT3 axis

Zhao, Chenggang; Yu, Huihan; Fan, Xiaoqing; Niu, Wanxiang; Fan, Jian‐Sheng; Sun, Suling; Gong, Meiting; Zhao, Bing; Fang, Zhiyou; Chen, Xueran

doi:10.1038/s41389-022-00402-w

Cited by 14 publications

(3 citation statements)

References 36 publications

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“…1 b–e). Drug resistance due to alterations in the cell stemness phenotype during cancer treatment has been widely reported 17 – 19 . The sphere formation assay revealed that individual HGC-27-LR cells exhibited a greater capacity for self-renewal and cellular aggregation into clusters compared to individual HGC-27 cells (Fig.…”

Section: Resultsmentioning

confidence: 99%

Long noncoding RNA NONHSAT160169.1 promotes resistance via hsa-let-7c-3p/SOX2 axis in gastric cancer

Zhao,

Xu,

Meng

et al. 2023

Sci Rep

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In clinical trials involving patients with HER2 (ERBB2 receptor tyrosine kinase 2) positive gastric cancer, the efficacy of the HER2-targeted drug lapatinib has proven to be disappointingly poor. Under the persistent pressure exerted by targeted drug therapy, a subset of tumor cells exhibit acquired drug resistance through the activation of novel survival signaling cascades, alongside the proliferation of tumor cells that previously harbored mutations conferring resistance to the drug. This study was undertaken with the aim of elucidating in comprehensive detail the intricate mechanisms behind adaptive resistance and identifying novel therapeutic targets that hold promise in the development of effective lapatinib-based therapies for the specific subset of patients afflicted with gastric cancer. We have successfully established a gastric cancer cell line with acquired lapatinib resistance, designated as HGC-27-LR cells. Utilizing comprehensive coding and noncoding transcriptome sequencing analysis, we have identified key factors that regulate lapatinib resistance in HGC-27 cells. We have compellingly validated that among all the lncRNAs identified in HGC-27-LR cells, a novel lncRNA (long noncoding RNA) named NONHSAT160169.1 was found to be most notably upregulated following exposure to lapatinib treatment. The upregulation of NONHSAT160169.1 significantly augmented the migratory, invasive, and stemness capabilities of HGC-27-LR cells. Furthermore, we have delved into the mechanism by which NONHSAT160169.1 regulates lapatinib resistance. The findings have revealed that NONHSAT160169.1, which is induced by the p-STAT3 (signal transducer and activator of transcription 3) nuclear transport pathway, functions as a decoy that competitively interacts with hsa-let-7c-3p and thereby abrogates the inhibitory effect of hsa-let-7c-3p on SOX2 (SRY-box transcription factor 2) expression. Hence, our study has unveiled the NONHSAT160169.1/hsa-let-7c-3p/SOX2 signaling pathway as a novel and pivotal axis for comprehending and surmounting lapatinib resistance in the treatment of HER2-positive gastric cancer.

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Section: Resultsmentioning

confidence: 99%

Long noncoding RNA NONHSAT160169.1 promotes resistance via hsa-let-7c-3p/SOX2 axis in gastric cancer

Zhao,

Xu,

Meng

et al. 2023

Sci Rep

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“…612 ZDHHC3 Golgi Palmitoylation of PD-L1 by ZDHHC3 inhibits antitumor immunity in vitro 613 ; palmitoylation of ACE2 by ZDHHC3 is critical for the membrane-targeting of extracellular vesicles secretion 614 ; elevated expression of ZDHHC3 is correlated with poor survival in breast cancer 615 ; high ZDHHC3 levels inhibits synaptic plasticity and memory in high-fat diet (HFD) mice 616 ; ZDHHC3 regulates the infection of primary and latent herpes simplex Virus 1. 617 ZDHHC4 ER, Golgi ZDHHC4 palmitoylates KAI1 and affects its localization, inhibiting angiogenesis 618 ; GSK3β palmitoylation mediated by ZDHHC4 promotes tumorigenicity of GBM stem cells 619 ; palmitoylation of D2R by ZDDHC4 is important for cell surface expression of the receptor. 643 ; the expression of ZDHHC14 is inhibited, leading to increased proliferation and decreased apoptosis in coronary artery disease 644 ; ZDHHC14 is involved in the palmitoylation of SARS-CoV-2 spike protein and contributes to virus entry.…”

Section: Genementioning

confidence: 99%

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

Zhong

Xiao

Xie

et al. 2023

MedComm

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Protein posttranslational modifications (PTMs) refer to the breaking or generation of covalent bonds on the backbones or amino acid side chains of proteins and expand the diversity of proteins, which provides the basis for the emergence of organismal complexity. To date, more than 650 types of protein modifications, such as the most well‐known phosphorylation, ubiquitination, glycosylation, methylation, SUMOylation, short‐chain and long‐chain acylation modifications, redox modifications, and irreversible modifications, have been described, and the inventory is still increasing. By changing the protein conformation, localization, activity, stability, charges, and interactions with other biomolecules, PTMs ultimately alter the phenotypes and biological processes of cells. The homeostasis of protein modifications is important to human health. Abnormal PTMs may cause changes in protein properties and loss of protein functions, which are closely related to the occurrence and development of various diseases. In this review, we systematically introduce the characteristics, regulatory mechanisms, and functions of various PTMs in health and diseases. In addition, the therapeutic prospects in various diseases by targeting PTMs and associated regulatory enzymes are also summarized. This work will deepen the understanding of protein modifications in health and diseases and promote the discovery of diagnostic and prognostic markers and drug targets for diseases.

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“…Acting downstream of ERK and AKT, glycogen synthase kinase 3β (GSK3β), a serine/threonine protein kinase, is also considered as a key hub for promoting malignancy of GSCs [ 104 , 105 ]. Zhao et al found that roles of GSK3β are affected by palmitoylation when ZDHHC4 palmitoylates GSK3β at the Cys14 residue [ 106 ]. Mechanistically, palmitoylation of GSK3β negatively affected binding of GSK3β to AKT1 and S6K kinases, thereby releasing the inhibitory roles of AKT1 and S6K on GSK3β.…”

Section: Palmitoylation In Cancermentioning

confidence: 99%

Diverse Roles of Protein Palmitoylation in Cancer Progression, Immunity, Stemness, and Beyond

Li,

Zhang,

Chen

2023

Cells

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Protein S-palmitoylation, a type of post-translational modification, refers to the reversible process of attachment of a fatty acyl chain—a 16-carbon palmitate acid—to the specific cysteine residues on target proteins. By adding the lipid chain to proteins, it increases the hydrophobicity of proteins and modulates protein stability, interaction with effector proteins, subcellular localization, and membrane trafficking. Palmitoylation is catalyzed by a group of zinc finger DHHC-containing proteins (ZDHHCs), whereas depalmitoylation is catalyzed by a family of acyl-protein thioesterases. Increasing numbers of oncoproteins and tumor suppressors have been identified to be palmitoylated, and palmitoylation is essential for their functions. Understanding how palmitoylation influences the function of individual proteins, the physiological roles of palmitoylation, and how dysregulated palmitoylation leads to pathological consequences are important drivers of current research in this research field. Further, due to the critical roles in modifying functions of oncoproteins and tumor suppressors, targeting palmitoylation has been used as a candidate therapeutic strategy for cancer treatment. Here, based on recent literatures, we discuss the progress of investigating roles of palmitoylation in regulating cancer progression, immune responses against cancer, and cancer stem cell properties.

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GSK3β palmitoylation mediated by ZDHHC4 promotes tumorigenicity of glioblastoma stem cells in temozolomide-resistant glioblastoma through the EZH2–STAT3 axis

Cited by 14 publications

References 36 publications

Long noncoding RNA NONHSAT160169.1 promotes resistance via hsa-let-7c-3p/SOX2 axis in gastric cancer

Long noncoding RNA NONHSAT160169.1 promotes resistance via hsa-let-7c-3p/SOX2 axis in gastric cancer

Protein posttranslational modifications in health and diseases: Functions, regulatory mechanisms, and therapeutic implications

Diverse Roles of Protein Palmitoylation in Cancer Progression, Immunity, Stemness, and Beyond

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