ZDHHC12 regulates tumor properties through YAP1 in glioblastoma

Qixiang ZHANG; Yongping YOU

doi:10.19401/j.cnki.1007-3639.2022.06.007

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ZDHHC12 regulates tumor properties through YAP1 in glioblastoma

Article | 更新时间：2025-12-31

- ZDHHC12 regulates tumor properties through YAP1 in glioblastoma
- China Oncology Vol. 32, Issue 6, Pages: 527-534(2022)
- 作者机构：
  
  南京医科大学第一附属医院神经外科,江苏南京 210029
- 作者简介：
- 基金信息：
- DOI：10.19401/j.cnki.1007-3639.2022.06.007
  CLC： R739.4
- Revised：2022-05-04，
  
  Published：30 June 2022
- 稿件说明：
移动端阅览
Qixiang ZHANG, Yongping YOU. ZDHHC12 regulates tumor properties through YAP1 in glioblastoma[J]. China Oncology, 2022, 32(6): 527-534.
DOI：

Qixiang ZHANG, Yongping YOU. ZDHHC12 regulates tumor properties through YAP1 in glioblastoma[J]. China Oncology, 2022, 32(6): 527-534. DOI： 10.19401/j.cnki.1007-3639.2022.06.007.

摘要

背景和目的：

胶质母细胞瘤（glioblastoma

GBM）是目前常见的恶性脑部肿瘤之一

但GBM相关发病机制仍不完全清楚。本研究旨在分析锌指DHHC结构域蛋白（zinc finger DHHC domain-containing protein

ZDHHC）12对Yes相关蛋白1（Yes-associated protein 1

YAP1）的调控

以及ZDHHC12/YAP1轴对GBM肿瘤特性的调控。

方法：

在癌症基因组图谱（The Cancer Genome Atlas

TCGA）数据库以及基因型-组织表达（Genotype-Tissue Expression

GTEx）数据库中分析ZDHHC12分别在正常脑组织及GBM中的表达情况

运用蛋白质印迹法（Western blot）以及实时荧光定量聚合酶链反应（real-time fluorescence quantitative polymerase chain reaction

RTFQ-PCR）检测

分析在U87、U251以及人正常星形胶质细胞（NHA）的mRNA表达及蛋白水平。在U87和U251两种GBM细胞系中通过设计的小干扰RNA（small interfering RNA

siRNA）敲低ZDHHC12

并验证YAP1蛋白水平的变化。通过免疫共沉淀（co-immunoprecipitation

Co-IP）验证内源性及外源性ZDHHC12及YAP1的相互关系。通过细胞计数试剂盒-8（cell counting kit-8

CCK-8）实验、细胞平板克隆形成实验、划痕实验分析GBM细胞敲低ZDHHC12后在增殖及迁移能力上发生的改变。检测在敲低ZDHHC12后GBM细胞系中上皮-间质转化（epithelial-mesenchymal transition

EMT）标志物变化。分析ZDHHC12对GBM患者预后的影响。并检测在不同组织样本中ZDHHC12和YAP1蛋白水平。

结果：

TCGA数据库及GTEx数据

库分析结果显示

ZDHHC12在GBM中的表达量明显高于正常脑组织（

0.01）

GBM细胞系中ZDHHC12的mRNA表达及蛋白水平高于NHA细胞系。U87和U251两组GBM细胞系中ZDHHC12的敲低会引起YAP1蛋白水平的降低。Co-IP实验验证了ZDHHC12及YAP1蛋白的相互关系。敲低ZDHHC12的表达能够显著抑制GBM细胞的增殖和迁移能力

差异有统计学意义（

0.05）。ZDHHC12的敲低也可以引起EMT相关标志物的改变。YAP1的回复可以逆转敲低ZDHHC12所引起的GBM肿瘤特性变化。TCGA数据库中

ZDHHC12的表达也与GBM患者的预后密切相关。在组织中ZDHHC12的表达也与YAP1表达呈高度正相关。

结论：

ZDHHC12在GBM中高表达且与YAP1呈正相关

ZDHHC12/YAP1轴可以调控GBM相关肿瘤特性。

Abstract

Background and purpose:

Glioblastoma (GBM) is one of the most malignant brain tumors

however

the pathogenesis of GBM has not been thoroughly studied. The purpose of this study was to analyze the regulation of Yes-associated protein 1 (YAP1) by zinc finger DHHC domain-containing protein 12 (ZDHHC12)

and the regulation of GBM tumor characteristics through the ZDHHC12/YAP1 axis.

Methods:

The expression of ZDHHC12 in normal brain tissue and GBM was analyzed in the The Cancer Genome Atlas (TCGA) database and Genotype-Tissue Expression (GTEx) database. Western blot and real-time fluorescence quantitative polymerase chain reaction (RTFQ-PCR) were used to detect the mRNA expression and protein levels in U87

U251 and NHA. ZDHHC12 was knocked down by designed siRNA in two GBM cell lines

U87 and U251

and the protein levels of YAP1 were detected. The interaction between endogenous and exogenous ZDHHC12 and YAP1 was verified by co-immunoprecipitation (Co-IP). The changes in proliferation and migration ability of GBM cells after knockdown of ZDHHC12 and restoration of YAP1 were analyzed by cell counting kit-8 (CCK-8) assay

cell plate clone formation assay and scratch assay. Changes in markers of epithelial-mesenchymal transition (EMT) in GBM cell lines after knockdown of ZDHHC12 and restoration of YAP1 were detected. The effect of ZDHHC12 on the prognosis of GBM patients was analyzed

and detection of the protein levels of ZDHHC12 and YAP1 in different tissue samples was carried out.

Results:

The analysis results of TCGA database and GTEx database showed that the expression of ZDHHC12 was significantly higher in GBM than in normal brain tissue (

0.01)

and the mRNA and protein levels of ZDHHC12 were higher in GBM cell lines than in NHAs cell lines. Knockdown of ZDHHC12 in both U87 and U251 GBM cell lines caused a decrease in YAP1 protein levels. Co-IP experiments verified the interaction between ZDHHC12 and YAP1 proteins. Knockdown of ZDHHC12 could significantly inhibit the proliferation and migration of GBM cells

and the difference was statistically significant (

0.05). Knockdown of ZDHHC12 also caused changes in EMT-related markers. Restoration of YAP1 reversed the changes in GBM tumor properties induced by the knockdown of ZDHHC12. In the TCGA database

the expression of ZDHHC12 was also closely related to the prognosis of GBM patients. The expression of ZDHHC12 in tissues was positively correlated with YAP1 expression.

Conclusion:

ZDHHC12 is highly expressed in GBM and positively related to YAP1

and the ZDHHC12/YAP1 axis regulates GBM tumor characteristics.

关键词

Keywords

references

ALEXANDER B M , CLOUGHESY T F . Adult glioblastoma [J ] . J Clin Oncol , 2017 , 35 ( 21 ): 2402 - 2409 . DOI: 10.1200/JCO.2017.73.0119 http://doi.org/10.1200/JCO.2017.73.0119 https://ascopubs.org/doi/10.1200/JCO.2017.73.0119 https://ascopubs.org/doi/10.1200/JCO.2017.73.0119

LAMOUILLE S , XU J , DERYNCK R . Molecular mechanisms of epithelial-mesenchymal transition [J ] . Nat Rev Mol Cell Biol , 2014 , 15 ( 3 ): 178 - 196 . DOI: 10.1038/nrm3758 http://doi.org/10.1038/nrm3758 https://doi.org/10.1038/nrm3758 https://doi.org/10.1038/nrm3758

ZANCONATO F , CORDENONSI M , PICCOLO S . YAP/TAZ at the roots of cancer [J ] . Cancer Cell , 2016 , 29 ( 6 ): 783 - 803 . DOI: 10.1016/j.ccell.2016.05.005 http://doi.org/10.1016/j.ccell.2016.05.005 https://linkinghub.elsevier.com/retrieve/pii/S1535610816302100 https://linkinghub.elsevier.com/retrieve/pii/S1535610816302100

ZHAO M , ZHANG Y , JIANG Y , et al . YAP promotes autophagy and progression of gliomas via upregulating HMGB1 [J ] . J Exp Clin Cancer Res , 2021 , 40 ( 1 ): 99 . DOI: 10.1186/s13046-021-01897-8 http://doi.org/10.1186/s13046-021-01897-8 https://doi.org/10.1186/s13046-021-01897-8 https://doi.org/10.1186/s13046-021-01897-8

GUICHET P O , MASLIANTSEV K , TACHON G , et al . Fatal correlation between YAP1 expression and glioma aggressiveness: clinical and molecular evidence [J ] . J Pathol , 2018 , 246 ( 2 ): 205 - 216 . DOI: 10.1002/path.5133 http://doi.org/10.1002/path.5133 https://onlinelibrary.wiley.com/doi/10.1002/path.5133 https://onlinelibrary.wiley.com/doi/10.1002/path.5133

FU W W , ZHAO P , LI H , et al . Bazedoxifene enhances paclitaxel efficacy to suppress glioblastoma via altering Hippo/YAP pathway [J ] . J Cancer , 2020 , 11 ( 3 ): 657 - 667 . DOI: 10.7150/jca.38350 http://doi.org/10.7150/jca.38350 http://www.jcancer.org/v11p0657.htm http://www.jcancer.org/v11p0657.htm

ROTH A F , WAN J M , BAILEY A O , et al . Global analysis of protein palmitoylation in yeast [J ] . Cell , 2006 , 125 ( 5 ): 1003 - 1013 . DOI: 10.1016/j.cell.2006.03.042 http://doi.org/10.1016/j.cell.2006.03.042 https://linkinghub.elsevier.com/retrieve/pii/S0092867406005150 https://linkinghub.elsevier.com/retrieve/pii/S0092867406005150

KO P J , DIXON S J . Protein palmitoylation and cancer [J ] . EMBO Rep , 2018 , 19 ( 10 ): e46666.

MIZUMARU C , SAITO Y , ISHIKAWA T , et al . Suppression of APP-containing vesicle trafficking and production of beta-amyloid by AID/DHHC-12 protein [J ] . J Neurochem , 2009 , 111 ( 5 ): 1213 - 1224 . DOI: 10.1111/j.1471-4159.2009.06399.x http://doi.org/10.1111/j.1471-4159.2009.06399.x https://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2009.06399.x https://onlinelibrary.wiley.com/doi/10.1111/j.1471-4159.2009.06399.x

YUAN M , CHEN X B , SUN Y T , et al . ZDHHC12-mediated claudin-3 S -palmitoylation determines ovarian cancer progression [J ] . Acta Pharm Sin B , 2020 , 10 ( 8 ): 1426 - 1439 . DOI: 10.1016/j.apsb.2020.03.008 http://doi.org/10.1016/j.apsb.2020.03.008 https://linkinghub.elsevier.com/retrieve/pii/S2211383520305451 https://linkinghub.elsevier.com/retrieve/pii/S2211383520305451

OMURO A , DEANGELIS L M . Glioblastoma and other malignant gliomas: a clinical review [J ] . JAMA , 2013 , 310 ( 17 ): 1842 - 1850 . DOI: 10.1001/jama.2013.280319 http://doi.org/10.1001/jama.2013.280319 http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2013.280319 http://jama.jamanetwork.com/article.aspx?doi=10.1001/jama.2013.280319

LE RHUN E , PREUSSER M , ROTH P , et al . Molecular targeted therapy of glioblastoma [J ] . Cancer Treat Rev , 2019 , 80 : 101896 . DOI: 10.1016/j.ctrv.2019.101896 http://doi.org/10.1016/j.ctrv.2019.101896 https://linkinghub.elsevier.com/retrieve/pii/S0305737219301124 https://linkinghub.elsevier.com/retrieve/pii/S0305737219301124

AIELLO N M , KANG Y B . Context-dependent EMT programs in cancer metastasis [J ] . J Exp Med , 2019 , 216 ( 5 ): 1016 - 1026 . DOI: 10.1084/jem.20181827 http://doi.org/10.1084/jem.20181827 https://rupress.org/jem/article/216/5/1016/121025/Contextdependent-EMT-programs-in-cancer https://rupress.org/jem/article/216/5/1016/121025/Contextdependent-EMT-programs-in-cancer

JIANG S Y , WANG X T , SONG D L , et al . Cholesterol induces epithelial-to-mesenchymal transition of prostate cancer cells by suppressing degradation of EGFR through APMAP [J ] . Cancer Res , 2019 , 79 ( 12 ): 3063 - 3075 .

FAN L G , CHEN Z X , WU X T , et al. Ubiquitin-specific protease 3 promotes glioblastoma cell invasion and epithelial-mesenchymal transition via stabilizing snail [J ] . Mol Cancer Res , 2019 , 17 ( 10 ): 1975 - 1984 . DOI: 10.1158/1541-7786.MCR-19-0197 http://doi.org/10.1158/1541-7786.MCR-19-0197 https://aacrjournals.org/mcr/article/17/10/1975/89925/Ubiquitin-Specific-Protease-3-Promotes https://aacrjournals.org/mcr/article/17/10/1975/89925/Ubiquitin-Specific-Protease-3-Promotes

PAN D J . The hippo signaling pathway in development and cancer [J ] . Dev Cell , 2010 , 19 ( 4 ): 491 - 505 . DOI: 10.1016/j.devcel.2010.09.011 http://doi.org/10.1016/j.devcel.2010.09.011 https://linkinghub.elsevier.com/retrieve/pii/S1534580710004296 https://linkinghub.elsevier.com/retrieve/pii/S1534580710004296

HONG W J , GUAN K L . The YAP and TAZ transcription co-activators: key downstream effectors of the mammalian Hippo pathway [J ] . Semin Cell Dev Biol , 2012 , 23 ( 7 ): 785 - 793 . DOI: 10.1016/j.semcdb.2012.05.004 http://doi.org/10.1016/j.semcdb.2012.05.004 https://linkinghub.elsevier.com/retrieve/pii/S108495211200105X https://linkinghub.elsevier.com/retrieve/pii/S108495211200105X

SHIBATA M , HAM K , HOQUE M O . A time for YAP1: tumorigenesis, immunosuppression and targeted therapy [J ] . Int J Cancer , 2018 , 143 ( 9 ): 2133 - 2144 . DOI: 10.1002/ijc.31561 http://doi.org/10.1002/ijc.31561 https://onlinelibrary.wiley.com/doi/10.1002/ijc.31561 https://onlinelibrary.wiley.com/doi/10.1002/ijc.31561

WANG Y , PAN P , WANG Z H , et al . Β-catenin-mediated YAP signaling promotes human glioma growth [J ] . J Exp Clin Cancer Res , 2017 , 36 ( 1 ): 136 . DOI: 10.1186/s13046-017-0606-1 http://doi.org/10.1186/s13046-017-0606-1 http://jeccr.biomedcentral.com/articles/10.1186/s13046-017-0606-1 http://jeccr.biomedcentral.com/articles/10.1186/s13046-017-0606-1

ZHANG Y , XIE P , WANG X , et al . YAP promotes migration and invasion of human glioma cells [J ] . J Mol Neurosci , 2018 , 64 ( 2 ): 262 - 272 . DOI: 10.1007/s12031-017-1018-6 http://doi.org/10.1007/s12031-017-1018-6 http://link.springer.com/10.1007/s12031-017-1018-6 http://link.springer.com/10.1007/s12031-017-1018-6

ARTINIAN N , CLONINGER C , HOLMES B , et al . Phosphorylation of the hippo pathway component AMOTL2 by the mTORC2 kinase promotes YAP signaling, resulting in enhanced glioblastoma growth and invasiveness [J ] . J Biol Chem , 2015 , 290 ( 32 ): 19387 - 19401 . DOI: 10.1074/jbc.M115.656587 http://doi.org/10.1074/jbc.M115.656587 https://linkinghub.elsevier.com/retrieve/pii/S0021925820421994 https://linkinghub.elsevier.com/retrieve/pii/S0021925820421994

LEE S , KANG H , SHIN E , et al . BEX1 and BEX4 induce GBM progression through regulation of actin polymerization and activation of YAP/TAZ signaling [J ] . Int J Mol Sci , 2021 , 22 ( 18 ): 9845 . DOI: 10.3390/ijms22189845 http://doi.org/10.3390/ijms22189845 https://www.mdpi.com/1422-0067/22/18/9845 https://www.mdpi.com/1422-0067/22/18/9845

MELHUISH T A , KOWALCZYK I , MANUKYAN A , et al . Myt1 and Myt1l transcription factors limit proliferation in GBM cells by repressing YAP1 expression [J ] . Biochim Biophys Acta Gene Regul Mech , 2018 , 1861 ( 11 ): 983 - 995 . DOI: 10.1016/j.bbagrm.2018.10.005 http://doi.org/10.1016/j.bbagrm.2018.10.005 https://linkinghub.elsevier.com/retrieve/pii/S1874939918302566 https://linkinghub.elsevier.com/retrieve/pii/S1874939918302566

ZHANG Z X , LI X , YANG F , et al . DHHC9-mediated GLUT1 S-palmitoylation promotes glioblastoma glycolysis and tumorigenesis [J ] . Nat Commun , 2021 , 12 ( 1 ): 5872 . DOI: 10.1038/s41467-021-26180-4 http://doi.org/10.1038/s41467-021-26180-4 https://doi.org/10.1038/s41467-021-26180-4 https://doi.org/10.1038/s41467-021-26180-4

CHEN X R , MA H H , WANG Z , et al. EZH2 palmitoylation mediated by ZDHHC5 in p 53-mutant glioma drives malignant development and progression [J ] . Cancer Res , 2017 , 77 ( 18 ): 4998 - 5010 .

FAN X Q , YANG H R , ZHAO C G , et al . Local anesthetics impair the growth and self-renewal of glioblastoma stem cells by inhibiting ZDHHC15-mediated GP130 palmitoylation [J ] . Stem Cell Res Ther , 2021 , 12 ( 1 ): 107 . DOI: 10.1186/s13287-021-02175-2 http://doi.org/10.1186/s13287-021-02175-2 https://doi.org/10.1186/s13287-021-02175-2 https://doi.org/10.1186/s13287-021-02175-2

CHEN X R , HAO A J , LI X , et al . Activation of JNK and p38 MAPK mediated by ZDHHC17 drives glioblastoma multiforme development and malignant progression [J ] . Theranostics , 2020 , 10 ( 3 ): 998 - 1015 . DOI: 10.7150/thno.40076 http://doi.org/10.7150/thno.40076 http://www.thno.org/v10p0998.htm http://www.thno.org/v10p0998.htm

CHEN X R , HU L , YANG H R , et al . DHHC protein family targets different subsets of glioma stem cells in specific niches [J ] . J Exp Clin Cancer Res , 2019 , 38 ( 1 ): 25 . DOI: 10.1186/s13046-019-1033-2 http://doi.org/10.1186/s13046-019-1033-2 https://doi.org/10.1186/s13046-019-1033-2 https://doi.org/10.1186/s13046-019-1033-2

SHEN Z C , WU P F , WANG F , et al . Gephyrin palmitoylation in basolateral amygdala mediates the anxiolytic action of benzodiazepine [J ] . Biol Psychiatry , 2019 , 85 ( 3 ): 202 - 213 . DOI: 10.1016/j.biopsych.2018.09.024 http://doi.org/10.1016/j.biopsych.2018.09.024 https://linkinghub.elsevier.com/retrieve/pii/S000632231831895X https://linkinghub.elsevier.com/retrieve/pii/S000632231831895X

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