The different role of YKL-40 in glioblastoma is a function of MGMT promoter methylation status
| Autor: | Wei Zhang, James Wang, Yan-bing Yu, Jian-nan Lv, Hua Han, Weiping Liu, En-ming Kang, Xiang Zhang, Wei-jun Chen, Yu-lian Zhang, Guihuai Wang, Xiao-sheng He |
|---|---|
| Rok vydání: | 2020 |
| Předmět: |
Adult
Male endocrine system Cancer Research IDH1 Methyltransferase Tumor suppressor gene DNA damage Immunology Biology medicine.disease_cause Methylation Article Epigenesis Genetic Cellular and Molecular Neuroscience Cancer stem cell Temozolomide medicine Humans Chitinase-3-Like Protein 1 Epigenetics lcsh:QH573-671 Promoter Regions Genetic DNA Modification Methylases neoplasms Brain Neoplasms Cancer stem cells lcsh:Cytology Tumor Suppressor Proteins Cell Biology DNA Methylation Middle Aged digestive system diseases CNS cancer DNA Repair Enzymes Drug Resistance Neoplasm Cancer research Female Neoplasm Recurrence Local Glioblastoma Carcinogenesis medicine.drug |
| Zdroj: | Cell Death and Disease, Vol 11, Iss 8, Pp 1-13 (2020) Cell Death & Disease |
| ISSN: | 2041-4889 |
| DOI: | 10.1038/s41419-020-02909-9 |
| Popis: | Inter- and intratumoral heterogeneity is a hallmark of glioblastoma (GBM) that facilitates recurrence, treatment resistance, and worse prognosis. O6-methylguanine-DNA methyltransferase (MGMT) promoter methylation is a significant prognostic marker for Temozolomide (TMZ) resistance in GBM patients. YKL-40 is a molecular marker for the mesenchymal subtype of GBMs and is responsible for TMZ resistance. However, underlying mechanisms by which MGMT epigenetics impacts patient outcomes and the function of YKL-40 are not fully determined. Herein, we performed in vitro and in vivo experiments, six human IDH1/2 wild-type glioblastoma stem-like cells (GSCs) were established and studied to further determine a potential interaction of YKL-40 and MGMT promoter methylation. We demonstrated that YKL-40 functioned differently in human IDH1/2 wild-type GSCs. In MGMT promoter-methylated (MGMT-m) GSCs, it acted as a tumor suppressor gene. On the other hand, in MGMT promoter-unmethylated (MGMT-um) GSCs, it promoted tumorigenesis. Notably, the reason that YKL-40 played different roles in GSCs could not be interpreted by the molecular classification of each GSCs, but is a function of MGMT promoter methylation status and involves the RAS–MEK–ERK pathway. YKL-40 mediated TMZ sensitivity by activating DNA damage responses (DDRs) in MGMT-m GSCs, and it mediated resistance to TMZ by inhibiting DDRs in MGMT-um GSCs. Our report demonstrated that MGMT promoter methylation status might influence a gene’s function in human cancer. Moreover, our data also highlight the point that gene function should be investigated not only according to the molecular tumor classification, but also the epigenetic signature. |
| Databáze: | OpenAIRE |
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