EZH2 Palmitoylation Mediated by ZDHHC5 in p53-Mutant Glioma Drives Malignant Development and Progression

Xueran Chen; Huihui Ma; Zhen Wang; Shangrong Zhang; Haoran Yang; Zhiyou Fang

doi:10.1158/0008-5472.CAN-17-1139

EZH2 Palmitoylation Mediated by ZDHHC5 in p53-Mutant Glioma Drives Malignant Development and Progression

Cancer Res. 2017 Sep 15;77(18):4998-5010. doi: 10.1158/0008-5472.CAN-17-1139. Epub 2017 Aug 3.

Authors

Xueran Chen^{1

2}, Huihui Ma^{3

4}, Zhen Wang^{5

2}, Shangrong Zhang^{5

2}, Haoran Yang^{5

3}, Zhiyou Fang^{1

2}

Affiliations

¹ Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, China. xueranchen@cmpt.ac.cn z.fang@cmpt.ac.cn.
² Cancer Hospital, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, China.
³ Key Laboratory of Ion Beam Bioengineering, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, China.
⁴ Department of Radiation Oncology, First Affiliated Hospital, Anhui Medical University, Hefei, Anhui, China.
⁵ Anhui Province Key Laboratory of Medical Physics and Technology, Center of Medical Physics and Technology, Hefei Institutes of Physical Science, Chinese Academy of Sciences, Hefei, Anhui, China.

PMID: 28775165
DOI: 10.1158/0008-5472.CAN-17-1139

Abstract

Gliomas with mutant p53 occurring in 30% of glioma patients exhibit therapeutic resistance and poor outcomes. In this study, we identify a novel mechanism through which mutant p53 drives cancer cell survival and malignant growth. We documented overexpression of the zinc finger protein ZDHHC5 in glioma compared with normal brain tissue and that this event tightly correlated with p53 mutations. Mechanistic investigations revealed that mutant p53 transcriptionally upregulated ZDHHC5 along with the nuclear transcription factor NF-Y. These events contributed to the development of glioma by promoting the self-renewal capacity and tumorigenicity of glioma stem-like cells, by altering the palmitoylation and phosphorylation status of the tumor suppressor EZH2. Taken together, our work highlighted ZDHHC5 as a candidate therapeutic target for management of p53-mutated gliomas. Cancer Res; 77(18); 4998-5010. ©2017 AACR.

MeSH terms

Acyltransferases / genetics
Acyltransferases / metabolism*
Animals
Apoptosis
Biomarkers, Tumor
Brain Neoplasms / genetics
Brain Neoplasms / metabolism
Brain Neoplasms / pathology
Cell Cycle
Cell Movement
Cell Proliferation
Cell Transformation, Neoplastic / genetics
Cell Transformation, Neoplastic / metabolism
Cell Transformation, Neoplastic / pathology*
Enhancer of Zeste Homolog 2 Protein / genetics
Enhancer of Zeste Homolog 2 Protein / metabolism*
Gene Expression Regulation, Neoplastic
Glioma / genetics
Glioma / metabolism
Glioma / pathology*
Humans
Lipoylation
Mice
Mice, Nude
Mutation / genetics*
Neoplasm Invasiveness
Neoplasm Recurrence, Local / genetics
Neoplasm Recurrence, Local / metabolism
Neoplasm Recurrence, Local / pathology*
Neoplasm Staging
Prognosis
Survival Rate
Tumor Cells, Cultured
Tumor Suppressor Protein p53 / genetics*
Xenograft Model Antitumor Assays

Substances

Biomarkers, Tumor
TP53 protein, human
Tumor Suppressor Protein p53
EZH2 protein, human
Enhancer of Zeste Homolog 2 Protein
Acyltransferases
ZDHHC5 protein, human