Department of Pharmacology, University of Colorado Anschutz Medical Campus (AMC), Aurora, Colorado, USA.
Molecular Biology Graduate Program, University of Colorado AMC, Aurora, Colorado, USA.
Neuro Oncol. 2023 Dec 8;25(12):2287-2301. doi: 10.1093/neuonc/noad128.
Medulloblastoma is the most common pediatric brain malignancy. Patients with the Group 3 subtype of medulloblastoma (MB) often exhibit MYC amplification and/or overexpression and have the poorest prognosis. While Group 3 MB is known to be highly dependent on MYC, direct targeting of MYC remains elusive.
Patient gene expression data were used to identify highly expressed EYA2 in Group 3 MB samples, assess the correlation between EYA2 and MYC, and examine patient survival. Genetic and pharmacological studies were performed on EYA2 in Group 3 derived MB cell models to assess MYC regulation and viability in vitro and in vivo.
EYA2 is more highly expressed in Group 3 MB than other MB subgroups and is essential for Group 3 MB growth in vitro and in vivo. EYA2 regulates MYC expression and protein stability in Group 3 MB, resulting in global alterations of MYC transcription. Inhibition of EYA2 tyrosine phosphatase activity, using a novel small molecule inhibitor (NCGC00249987, or 9987), significantly decreases Group 3 MB MYC expression in both flank and intracranial growth in vivo. Human MB RNA-seq data show that EYA2 and MYC are significantly positively correlated, high EYA2 expression is significantly associated with a MYC transcriptional signature, and patients with high EYA2 and MYC expression have worse prognoses than those that do not express both genes at high levels.
Our data demonstrate that EYA2 is a critical regulator of MYC in Group 3 MB and suggest a novel therapeutic avenue to target this highly lethal disease.
髓母细胞瘤是最常见的小儿脑恶性肿瘤。患有髓母细胞瘤（MB）3 组亚型的患者通常表现为 MYC 扩增和/或过表达，且预后最差。虽然已知 3 组 MB 高度依赖 MYC，但直接针对 MYC 的靶向治疗仍难以实现。
利用患者的基因表达数据来鉴定 3 组 MB 样本中高度表达的 EYA2，评估 EYA2 与 MYC 的相关性，并检查患者的生存率。在 3 组衍生的 MB 细胞模型中对 EYA2 进行遗传和药理学研究，以评估 MYC 调节和体外及体内的生存能力。
EYA2 在 3 组 MB 中的表达水平高于其他 MB 亚组，并且是 3 组 MB 体外和体内生长所必需的。EYA2 调节 3 组 MB 中的 MYC 表达和蛋白稳定性，导致 MYC 转录的全局改变。使用新型小分子抑制剂（NCGC00249987，或 9987）抑制 EYA2 酪氨酸磷酸酶活性，可显著降低体内侧翼和颅内生长的 3 组 MB MYC 表达。人 MB RNA-seq 数据显示，EYA2 和 MYC 呈显著正相关，高 EYA2 表达与 MYC 转录特征显著相关，高 EYA2 和 MYC 表达的患者预后比不高表达这两个基因的患者差。
我们的数据表明，EYA2 是 3 组 MB 中 MYC 的关键调节因子，并提出了一种针对这种高度致命疾病的新的治疗途径。
