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

Lu, Feng; Shen, Shuiwen; Wu, Shizhong; Zheng, Pengfeng; Lin, Kun; Liao, Jingwei; Jiang, Xiaohang; Zeng, Guangming; Wei, De

doi:10.21037/atm-22-520

Cited by 11 publications

(5 citation statements)

References 43 publications

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“…DNA demethylation and upregulation of IGF2BP3 can be involved in the malignant progression of glioma ( 5 ). Alternated DNA methylation in ZDHHC12 is associated with migration and invasion capabilities in glioma cell lines ( 6 ). GPX8 expression was correlated to the reduced DNA methylation at the promoter region and might be related to cancer-associated fibroblasts and immune infiltration levels in glioma ( 7 ).…”

Section: Introductionmentioning

confidence: 99%

Integrated analysis of genome-wide DNA methylation and cancer-associated fibroblasts identified prognostic biomarkers and immune checkpoint blockade in lower grade gliomas

et al. 2023

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BackgroundCancer-associated fibroblasts (CAFs) are vital components of prominent cellular components in lower-grade gliomas (LGGs) that contribute to LGGs’ progression, treatment resistance, and immunosuppression. Epigenetic modification and immunity have significant implications for tumorigenesis and development.MethodsWe combined aberrant methylation and CAFs abundances to build a prognostic model and the impact on the biological properties of LGGs. Grouping based on the median CAFs abundances score of samples in the TCGA-LGGs dataset, differentially expressed genes and aberrantly methylated genes were combined for subsequent analysis.ResultsWe identified five differentially methylated and expressed genes (LAT32, SWAP70, GSAP, EMP3, and SLC2A10) and established a prognostic gene signature validated in the CGGA-LGGs dataset. Immunohistochemistry (IHC) and in vitro tests were performed to verify these expressions. The high-risk group increased in tumor-promoting immune cells and tumor mutational burden. Notably, risk stratification had different ICB sensitivities in LGGs, and there were also significant sensitivity differences for temozolomide and the other three novel chemotherapeutic agents.ConclusionOur study reveals characteristics of CAFs in LGGs, refines the direct link between epigenetics and tumor stroma, and might provide clinical implications for guiding tailored anti-CAFs therapy in combination with immunotherapy for LGGs patients.

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Section: Introductionmentioning

confidence: 99%

Integrated analysis of genome-wide DNA methylation and cancer-associated fibroblasts identified prognostic biomarkers and immune checkpoint blockade in lower grade gliomas

et al. 2023

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“… 38 ZDHHC21 regulates oxidative phosphorylation hyperactivity to induce differentiation block and stemness in acute myeloid leukemia cells. 39 It has been documented that high expression of ZDHHC12 is associated with poor prognosis in glioma and promotes malignant cell growth, 40 and that ZDHHC12‐mediated S‐palmitoylation of Claudin‐3 promotes ovarian cancer progression. 41 While previous studies have identified an oncogenic role for ZDHHC12, its potential involvement in the regulation of mitochondrial activity has not been reported until the present study.…”

Section: Discussionmentioning

confidence: 99%

Inhibition of palmitoyltransferase ZDHHC12 sensitizes ovarian cancer cells to cisplatin through ROS‐mediated mechanisms

Zhang,

Liao,

Wang

et al. 2024

Cancer Science

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Platinum‐based therapies have revolutionized the treatment of high‐grade serous ovarian cancer (HGSOC). However, high rates of disease recurrence and progression remain a major clinical concern. Impaired mitochondrial function and dysregulated reactive oxygen species (ROS), hallmarks of cancer, hold potential as therapeutic targets for selectively sensitizing cisplatin treatment. Here, we uncover an oncogenic role of the palmitoyltransferase ZDHHC12 in regulating mitochondrial function and ROS homeostasis in HGSOC cells. Analysis of The Cancer Genome Atlas (TCGA) ovarian cancer data revealed significantly elevated ZDHHC12 expression, demonstrating the strongest positive association with ROS pathways among all ZDHHC enzymes. Transcriptomic analysis of independent ovarian cancer datasets and the SNU119 cell model corroborated this association, highlighting a strong link between ZDHHC12 expression and signature pathways involving mitochondrial oxidative metabolism and ROS regulation. Knockdown of ZDHHC12 disrupted this association, leading to increased cellular complexity, ATP levels, mitochondrial activity, and both mitochondrial and cellular ROS. This dysregulation, achieved by the siRNA knockdown of ZDHHC12 or treatment with the general palmitoylation inhibitor 2BP or the fatty acid synthase inhibitor C75, significantly enhanced cisplatin cytotoxicity in 2D and 3D spheroid models of HGSOC through ROS‐mediated mechanisms. Markedly, ZDHHC12 inhibition significantly augmented the anti‐tumor activity of cisplatin in an ovarian cancer xenograft tumor model, as well as in an ascites‐derived organoid line of platinum‐resistant ovarian cancer. Our data suggest the potential of ZDHHC12 as a promising target to improve the outcome of HGSOCs in response to platinum‐based chemotherapy.

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“…Some zDHHCs have important implications in the immunotherapy of gliomas. zDHHC12 is also aberrantly expressed in gliomas, and knockdown of zDHHC12 reduces glioma cell survival, while overexpression of zDHHC12 not only promotes glioma cell growth but is also associated with immune cell infiltration ( Lu et al, 2022 ). In gliomas, immune cell infiltration leads to immunotherapy resistance.…”

Section: The Role Of Zdhhc In Neurological Diseasesmentioning

confidence: 99%

The role of s-palmitoylation in neurological diseases: implication for zDHHC family

Liao,

Huang,

Liu

et al. 2024

Front. Pharmacol.

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S-palmitoylation is a reversible posttranslational modification, and the palmitoylation reaction in human-derived cells is mediated by the zDHHC family, which is composed of S-acyltransferase enzymes that possess the DHHC (Asp-His-His-Cys) structural domain. zDHHC proteins form an autoacylation intermediate, which then attaches the fatty acid to cysteine a residue in the target protein. zDHHC proteins sublocalize in different neuronal structures and exert dif-ferential effects on neurons. In humans, many zDHHC proteins are closely related to human neu-rological disor-ders. This review focuses on a variety of neurological disorders, such as AD (Alz-heimer’s disease), HD (Huntington’s disease), SCZ (schizophrenia), XLID (X-linked intellectual disability), attention deficit hyperactivity disorder and glioma. In this paper, we will discuss and summarize the research progress regarding the role of zDHHC proteins in these neu-rological disorders.

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

Abstract: Contributions: (I) Conception and design: F Lu; (II) Administrative support: SH Shen; (III) Provision of study materials or patients: S Wu; (IV)

Cited by 11 publications

References 43 publications

Integrated analysis of genome-wide DNA methylation and cancer-associated fibroblasts identified prognostic biomarkers and immune checkpoint blockade in lower grade gliomas

Integrated analysis of genome-wide DNA methylation and cancer-associated fibroblasts identified prognostic biomarkers and immune checkpoint blockade in lower grade gliomas

Inhibition of palmitoyltransferase ZDHHC12 sensitizes ovarian cancer cells to cisplatin through ROS‐mediated mechanisms

The role of s-palmitoylation in neurological diseases: implication for zDHHC family

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