Overactivation of histone deacetylases and EZH2 in Wilms tumorigenesis
作者机构：Department of PediatricsTulane University School of MedicineNew OrleansLA 70112USA Department of Pathology and Laboratory MedicineTulane University School of MedicineNew OrleansLA 70112USA
出 版 物：《Genes & Diseases》 (基因与疾病（英文）)
年 卷 期：2023年第10卷第5期
页 面：1783-1786页
核心收录：
学科分类：1002[医学-临床医学] 100214[医学-肿瘤学] 10[医学]
基 金：supported by the American Heart Association(No.17SDG33660072) the Louisiana Board of Regents Support Fund(No.LEQSF-RD-A-18)to Dr.Hongbing Liu
摘 要：Wilms tumor (WT) is the most common childhood kidney cancer. Although WT is largely curable, current treatments fail in up to 15 percent of patients. Moreover, survivors suffer from the complications and late effects of the aggressive treatments. Thus, there is a critical need to improve our understanding of tumorigenesis to develop novel therapies to reduce the treatment burden while maintaining excellent survival rates. WT is believed to arise from the immature kidney cells, nephron progenitor cells (NPCs), which have failed to differentiate properly. Previous studies revealed that Wilms cells share a transcriptional and epigenetic landscape with normal renal stem cells.1 Although several studies have shown the positive associations between WT in children and embryonic exposure to adverse environments, the underlying mechanisms remain unknown. Altered epigenetics is central to oncogenesis in many pediatric cancers. The critical contribution of epigenetic dysregulation to pediatric tumors provides a compelling rationale for the therapeutic potential of epigenetic drugs. Histone deacetylases (HDACs) and Enhancer of Zeste Homolog 2 (EZH2, a histone H3K27 methyltransferase), have been demonstrated to play a critical role in self-renewal and differentiation of mouse NPCs.2,3 In addition, altered expression and mutations of HDACs and EZH2 have been linked to many human cancers, including WT. Thus, they are among the most promising therapeutic targets for cancer treatment. We reasoned that WT would result from the unrestrained proliferation of progenitor cells due to overactive HDAC1/2 (HDAC1 and HDAC2), and EZH2. We tested this hypothesis by analyzing a clinical specimen received from the left kidney tumor of an 11-year-old male patient diagnosed with WT and four other human WT specimens. We have the approval from Tulane Human Research Protection Office & Institutional Review Boards (Study number: 2019–623) to study WT specimens. The tumor (9.5 cm × 8 cm × 7.5 cm) is cl
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