Wadhwani Nitin, Nayak Sonali, Wang Yufen, Hashizume Rintaro, Jie Chunfa, Mania-Farnell Barbara, James Charles David, Xi Guifa, Tomita Tadanori
Department of Pathology, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Division of Pediatric Neurosurgery, Ann & Robert H. Lurie Children's Hospital of Chicago, Northwestern University Feinberg School of Medicine, Chicago, IL 60611, USA.
Cancers (Basel). 2023 Jun 30;15(13):3429. doi: 10.3390/cancers15133429.
Pediatric high-grade gliomas (pHGGs) are common malignant brain tumors without effective treatment and poor patient survival. Abnormal posttranslational modification at the histone H3 tail plays critical roles in tumor cell malignancy. We have previously shown that the trimethylation of lysine 4 at histone H3 (H3K4me3) plays a significant role in pediatric ependymoma malignancy and is associated with tumor therapeutic sensitivity. Here, we show that H3K4me3 and its methyltransferase WDR82 are elevated in pHGGs. A reduction in H3K4me3 by downregulating WDR82 decreases H3K4me3 promoter occupancy and the expression of genes associated with stem cell features, cell proliferation, the cell cycle, and DNA damage repair. A reduction in WDR82-mediated H3K4me3 increases the response of pediatric glioma cells to chemotherapy. These findings suggest that WDR82-mediated H3K4me3 is an important determinant of pediatric glioma malignancy and therapeutic response. This highlights the need for a more thorough understanding of the potential of WDR82 as an epigenetic target to increase therapeutic efficacy and improve the prognosis for children with malignant gliomas.
小儿高级别胶质瘤（pHGGs）是常见的恶性脑肿瘤，缺乏有效的治疗方法，患者生存率低。组蛋白H3尾部的异常翻译后修饰在肿瘤细胞恶性肿瘤中起关键作用。我们之前已经表明，组蛋白H3赖氨酸4位点的三甲基化（H3K4me3）在小儿室管膜瘤恶性肿瘤中起重要作用，并与肿瘤治疗敏感性相关。在这里，我们表明H3K4me3及其甲基转移酶WDR82在pHGGs中升高。通过下调WDR82降低H3K4me3可减少H3K4me3启动子占据以及与干细胞特征、细胞增殖、细胞周期和DNA损伤修复相关基因的表达。WDR82介导的H3K4me3减少增加了小儿胶质瘤细胞对化疗的反应。这些发现表明，WDR82介导的H3K4me3是小儿胶质瘤恶性肿瘤和治疗反应的重要决定因素。这凸显了更深入了解WDR82作为表观遗传靶点的潜力以提高治疗效果并改善恶性胶质瘤患儿预后的必要性。
