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

doi:10.21037/atm-22-520

. 2022 Mar;10(6):334.

doi: 10.21037/atm-22-520.

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

Feng Lu^#^{1

2}, Shang-Hang Shen^#³, Shizhong Wu^{1

2}, Pengfeng Zheng^{1

2}, Kun Lin^{1

2}, Jingwei Liao^{1

2}, Xiaohang Jiang^{1

2}, Guangming Zeng^{1

2}, De Wei^{1

4

2}

Affiliations

¹ Department of Neurosurgery, Fujian Provincial Hospital South Branch, Fuzhou, China.
² Department of Neurosurgery, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China.
³ Department of Neurosurgery, The First Affiliated Hospital of Xiamen University, Medical College of Xiamen University, Xiamen, China.
⁴ Department of Neurosurgery, Fujian Provincial Hospital, Fuzhou, China.

^# Contributed equally.

PMID: 35434031
PMCID: PMC9011314
DOI: 10.21037/atm-22-520

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

Feng Lu et al. Ann Transl Med. 2022 Mar.

. 2022 Mar;10(6):334.

doi: 10.21037/atm-22-520.

Authors

Feng Lu^#^{1

2}, Shang-Hang Shen^#³, Shizhong Wu^{1

2}, Pengfeng Zheng^{1

2}, Kun Lin^{1

2}, Jingwei Liao^{1

2}, Xiaohang Jiang^{1

2}, Guangming Zeng^{1

2}, De Wei^{1

4

2}

Affiliations

¹ Department of Neurosurgery, Fujian Provincial Hospital South Branch, Fuzhou, China.
² Department of Neurosurgery, Shengli Clinical Medical College of Fujian Medical University, Fuzhou, China.
³ Department of Neurosurgery, The First Affiliated Hospital of Xiamen University, Medical College of Xiamen University, Xiamen, China.
⁴ Department of Neurosurgery, Fujian Provincial Hospital, Fuzhou, China.

^# Contributed equally.

PMID: 35434031
PMCID: PMC9011314
DOI: 10.21037/atm-22-520

Abstract

Background: Glioma is the most common intracranial primary malignancy, characterized by abnormal signal transductions caused by transcriptional and post-transcriptional regulators. Studies show the palmitoylation of oncoproteins and tumor suppressors participate in cancer progression, while studies of protein S-palmitoyltransferases in glioma are limited. A systematic analysis of zinc finger DHHC-type palmitoyltransferases (ZDHHC) in glioma is still lacking.

Methods: A prognostic heatmap and Kaplan-Meier overall survival plot of 24 members of the ZDHHC family in pan-cancer created. The expression and prognostic significance of ZDHHC12 was analyzed by using Gene Expression Profiling Interactive Analysis (GEPIA) and PrognoScan. DBTRG and U251 cells with silenced ZDHHC12 expression were constructed and used for cell counting kit-8 (CCK-8), Transwell assay and wound healing assay in vitro.

Results: Here, we first conducted expression and prognostic analyses of 24 ZDHHCs from The Cancer Genome Atlas (TCGA), the Chinese Glioma Genome Atlas (CGGA), and other glioma datasets. We found ZDHHC12 to be the only unfavorable prognostic marker in glioma. The function of ZDHHC12 in glioma was then investigated with loss-of-function strategies and in vitro cell assays. Results showed that ZDHHC12 knockdown remarkably reduced the growth, migration, and invasion capabilities in DBTRG and U251 cell lines, suggesting that ZDHHC12 may contribute to malignant behavior in glioma cells. Finally, the molecular basis for ZDHHC12 expression in glioma was analyzed, and DNA hypomethylation was found to be responsible for increased ZDHHC12 mRNA expression and related prognoses.

Conclusions: ZDHHC12 positively promoted the proliferation and migration of glioma cells. Decreased DNA methylation may lead to increased ZDHHC12 expression in gliomas. This study may deepen the understanding of glioma progression and therapeutics.

Keywords: Glioma; ZDHHC12; hypomethylation; prognosis.

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Conflict of interest statement

Conflicts of Interest:All authors have completed the ICMJE uniform disclosure form (available at https://atm.amegroups.com/article/view/10.21037/atm-22-520/coif). The authors have no conflicts of interest to declare.

Figures

**Figure 1**
Analysis showing increased expression of ZDHHC12 as a hazardous marker in glioma. (A) Overall survival map of 24 members of the ZDHHC family. (B) Pan-cancer expression analysis showing upregulation of ZDHHC12 in multiple cancer types, including GBM and LGG. (C) Box plot showing significantly increased ZDHHC12 in GBM and LGG datasets. (D) Kaplan-Meier survival plot of ZDHHC12 in GBM and LGG. *, P<0.05. ZDHHC, zinc finger DHHC-type palmitoyltransferase; GBM, glioblastoma multiforme; LGG, low-grade glioma.

**Figure 2**
Expression and prognostic performance of ZDHHC12 in CGGA datasets. (A) Expression of ZDHHC12 in different histological types of glioma tissue. (B) Expression of ZDHHC12 in WHO grade II, III, and IV grades glioma tissue. (C) Abundance of ZDHHC12 in IDH mutant and wild-type glioma tissues. (D) ZDHHC12 expression in the 1p/19q co-deletion glioma tissue. (E) Kaplan-Meier survival plot of ZDHHC12 expression in patients with glioma. ZDHHC, zinc finger DHHC-type palmitoyltransferase; CGGA, the Chinese Glioma Gene Atlas; WHO, World Health Organization; IDH, isocitrate dehydrogenase.

**Figure 3**
Prognostic significance of ZDHHC12 in the GSE4271 (A) and GSE4412 (B) datasets. ZDHHC, zinc finger DHHC-type palmitoyltransferase.

**Figure 4**
Decreased ZDHHC12 attenuates the proliferation, invasion and migration in glioma cells. (A) The expression of ZDHHC12 was silenced in DBTRG and U251 glioma cells. (B) ZDHHC12 silencing repressed cell growth in DBTRG and U251 glioma cells. (C,D) Transwell assays showing that ZDHHC12 knockdown cells exhibited reduced invasion potential. The cells were stained with 1% crystal violet solution to observe the number of migrated cells. Magnification of image, 100×. (E,F) Wound healing assays demonstrating deceased migration ability in ZDHHC12 silenced glioma cells. ZDHHC, zinc finger DHHC-type palmitoyltransferase. *, P<0.05; **, P<0.01. Magnification of images, 40×.

**Figure 5**
Elevated DNA methylation may contribute to increased expression of ZDHHC12 in glioma. (A) The DNA methylation level of ZDHHC12 significantly decreased in different histological types of glioma tissue (CGGA datasets). (B) The DNA methylation level of ZDHHC12 significantly decreased in glioma tissues with a higher WHO grade (CGGA datasets). (C) The DNA methylation level of ZDHHC12 significantly decreased in IDH wild-type glioma tissues (CGGA datasets). (D) Kaplan-Merrier survival plot of ZDHHC12 methylation level in primary glioma (CGGA datasets). (E) Low amplification was observed in glioma samples (TCGA dataset). (F) Significant negative correlation was observed between ZDHHC12 methylation and expression level (TCGA dataset). ZDHHC, zinc finger DHHC-type palmitoyltransferase; CGGA, Chinese Glioma Genome Atlas; TCGA, the Cancer Genome Atlas, WHO, World Health Organization; IDH, isocitrate dehydrogenase.

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References

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[1] Wang H, Xu T, Huang Q, et al. Immunotherapy for Malignant Glioma: Current Status and Future Directions. Trends Pharmacol Sci 2020;41:123-38. 10.1016/j.tips.2019.12.003 - DOI - PubMed

[2] Wang H, Xu T, Huang Q, et al. Immunotherapy for Malignant Glioma: Current Status and Future Directions. Trends Pharmacol Sci 2020;41:123-38. 10.1016/j.tips.2019.12.003 - DOI - PubMed

[3] Weller M, Wick W, Aldape K, et al. Glioma. Nat Rev Dis Primers 2015;1:15017. 10.1038/nrdp.2015.17 - DOI - PubMed

[4] Weller M, Wick W, Aldape K, et al. Glioma. Nat Rev Dis Primers 2015;1:15017. 10.1038/nrdp.2015.17 - DOI - PubMed

[5] Nicholson JG, Fine HA. Diffuse Glioma Heterogeneity and Its Therapeutic Implications. Cancer Discov 2021;11:575-90. 10.1158/2159-8290.CD-20-1474 - DOI - PubMed

[6] Nicholson JG, Fine HA. Diffuse Glioma Heterogeneity and Its Therapeutic Implications. Cancer Discov 2021;11:575-90. 10.1158/2159-8290.CD-20-1474 - DOI - PubMed

[7] Dai C, Celestino JC, Okada Y, et al. PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev 2001;15:1913-25. 10.1101/gad.903001 - DOI - PMC - PubMed

[8] Dai C, Celestino JC, Okada Y, et al. PDGF autocrine stimulation dedifferentiates cultured astrocytes and induces oligodendrogliomas and oligoastrocytomas from neural progenitors and astrocytes in vivo. Genes Dev 2001;15:1913-25. 10.1101/gad.903001 - DOI - PMC - PubMed

[9] Tomiyama A, Ichimura K. Signal transduction pathways and resistance to targeted therapies in glioma. Semin Cancer Biol 2019;58:118-29. 10.1016/j.semcancer.2019.01.004 - DOI - PubMed

[10] Tomiyama A, Ichimura K. Signal transduction pathways and resistance to targeted therapies in glioma. Semin Cancer Biol 2019;58:118-29. 10.1016/j.semcancer.2019.01.004 - DOI - PubMed

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

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

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Conflict of interest statement

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