The different role of YKL-40 in glioblastoma is a function of MGMT promoter methylation status

• Published in: Cell death & disease 2020-08, Vol.11 (8), p.668, Article 668
• Main Authors: Chen, Wei-jun, Zhang, Xiang, Han, Hua, Lv, Jian-nan, Kang, En-ming, Zhang, Yu-lian, Liu, Wei-ping, He, Xiao-sheng, Wang, James, Wang, Gui-huai, Yu, Yan-bing, Zhang, Wei
• Format: Article
• Language: English
• Subjects: 13/100; 38/91; 631/532/71; 692/699/67/1922; Adult; Antibodies; Biochemistry; Biomedical and Life Sciences; Brain cancer; Brain Neoplasms - pathology; Cell Biology; Cell Culture; Chitinase-3-Like Protein 1 - metabolism; Chitinase-3-Like Protein 1 - physiology; Deoxyribonucleic acid; DNA; DNA damage; DNA methylation; DNA Methylation - genetics; DNA methyltransferase; DNA Modification Methylases - genetics; DNA Modification Methylases - metabolism; DNA Repair Enzymes - genetics; DNA Repair Enzymes - metabolism; Drug Resistance, Neoplasm - drug effects; Drug Resistance, Neoplasm - genetics; Epigenesis, Genetic - drug effects; Epigenetics; Female; Glioblastoma; Glioblastoma - metabolism; Glioblastoma - pathology; Humans; Immunology; Life Sciences; Male; Mesenchyme; Metabolic pathways; Methylation; Methylguanine; Middle Aged; Neoplasm Recurrence, Local - genetics; O6-methylguanine-DNA methyltransferase; Promoter Regions, Genetic - genetics; Temozolomide; Temozolomide - pharmacology; Temozolomide - therapeutic use; Treatment resistance; Tumor suppressor genes; Tumor Suppressor Proteins - genetics; Tumor Suppressor Proteins - metabolism; Tumorigenesis
• ISSN: 2041-4889; 2041-4889
• DOI: 10.1038/s41419-020-02909-9

Inter- and intratumoral heterogeneity is a hallmark of glioblastoma (GBM) that facilitates recurrence, treatment resistance, and worse prognosis. O 6 -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.