Abstract
Lysine to methionine mutations at position 27 (K27M) in the histone H3 (H3.3 and H3.1) are highly prevalent in pediatric high-grade gliomas (HGG) that arise in the midline of the central nervous system. H3K27M perturbs the activity of polycomb repressor complex 2 and correlates with DNA hypomethylation; however, the pathways whereby H3K27M drives the development of pediatric HGG remain poorly understood. To understand the mechanism of pediatric HGG development driven by H3.3K27M and discover potential therapeutic targets or biomarkers, we established pediatric glioma cell model systems harboring H3.3K27M and performed microarray analysis. H3.3K27M caused the upregulation of multiple cancer/testis (CT) antigens, such as ADAMTS1, ADAM23, SPANXA1, SPANXB1/2, IL13RA2, VCY, and VCX3A, in pediatric glioma cells. Chromatin immunoprecipitation analysis from H3.3K27M cells revealed decreased H3K27me3 levels and increased H3K4me3 levels on the VCX3A promoter. Knockdown of VCX3A by siRNA significantly inhibited the growth of pediatric glioma cells harboring H3.3K27M. Overexpression of VCX3A/B genes stimulated the expression of several HLA genes, including HLA-A, HLA-B, HLA-E, HLA-F, and HLA-G The expression of VCX3A in pediatric HGG was confirmed using a tissue microarray. Gene set enrichment analysis revealed that CT antigens are enriched in pediatric HGG clinical specimens with H3.3K27M, with the upregulation of IL13RA2 contributing to the enrichment significantly. These results indicate that the upregulation of CT antigens, such as VCX3A and IL13RA2, correlates with pediatric gliomagenesis. Mol Cancer Res; 16(4); 623-33. ©2018 AACR.
Highlights
Brain and central nervous system tumors are the leading causes of cancer-related death and the second most common cancers in children and adolescents aged birth to 19 years old [1]
We found H3.3K27M could activate the expression of multiple CT antigens in pediatric glioma cells, and demonstrated that interleukin 13 receptor subunit alpha 2 (IL13RA2) and members of the variable charge X/Y (VCX/Y) gene family were among the top upregulated genes in glioma cells stably expressing H3.3K27M
Constructs encoding a FLAG-tagged WT or K27M mutant form of histone H3.3 were stably transfected into pediatric glioma cells, Res259 (WHO grade II) or SF188 (WHO grade IV) cells, whereas the empty vector was stably transfected into cells to serve as controls
Summary
Brain and central nervous system tumors are the leading causes of cancer-related death and the second most common cancers in children and adolescents aged birth to 19 years old [1]. Among various childhood brain tumors, pediatric high-grade gliomas (HGG) is the deadliest type. Epigenetic changes, mutations in or altered expression of epigenetic machinery, have been implicated in the development of various cancers including pediatric HGG [2, 3]. Sequencing of pediatric HGG tumors revealed the c.83A>T mutations in H3F3A or HIST1H3B/C, which result in the lysine 27 to methionine (K27M) missense mutations in histone H3.3 or H3.1, respectively [4,5,6]. The H3K27M mutations are enriched in pediatric HGG residing in the midline structures, such as pontine, brainstem, thalamus, and spinal cord [7,8,9,10,11,12].
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