Fedele Vita, Dai Fangping, Masilamani Anie P, Heiland Dieter H, Kling Eva, Gätjens-Sanchez Ana M, Ferrarese Roberto, Platania Leonardo, Soroush Doostkam, Kim Hyunsoo, Nelander Sven, Weyerbrock Astrid, Prinz Marco, Califano Andrea, Iavarone Antonio, Bredel Markus, Carro Maria S
Department of Neurosurgery, Medical Center, University of Freiburg, Freiburg, Germany.
Faculty of Medicine, University of Freiburg, Freiburg, Germany.
Mol Cancer Res. 2017 Aug;15(8):998-1011. doi: 10.1158/1541-7786.MCR-16-0494. Epub 2017 May 16.
Glioblastoma (GBM) comprises distinct subtypes characterized by their molecular profile. Mesenchymal identity in GBM has been associated with a comparatively unfavorable prognosis, primarily due to inherent resistance of these tumors to current therapies. The identification of molecular determinants of mesenchymal transformation could potentially allow for the discovery of new therapeutic targets. Zinc Finger and BTB Domain Containing 18 (ZBTB18/ZNF238/RP58) is a zinc finger transcriptional repressor with a crucial role in brain development and neuronal differentiation. Here, ZBTB18 is primarily silenced in the mesenchymal subtype of GBM through aberrant promoter methylation. Loss of ZBTB18 contributes to the aggressive phenotype of glioblastoma through regulation of poor prognosis-associated signatures. Restitution of ZBTB18 expression reverses the phenotype and impairs tumor-forming ability. These results indicate that ZBTB18 functions as a tumor suppressor in GBM through the regulation of genes associated with phenotypically aggressive properties. This study characterizes the role of the putative tumor suppressor ZBTB18 and its regulation by promoter hypermethylation, which appears to be a common mechanism to silence ZBTB18 in the mesenchymal subtype of GBM and provides a new mechanistic opportunity to specifically target this tumor subclass. .
胶质母细胞瘤（GBM）由具有不同分子特征的亚型组成。GBM中的间充质特征与相对较差的预后相关，主要是因为这些肿瘤对当前治疗具有内在抗性。鉴定间充质转化的分子决定因素可能有助于发现新的治疗靶点。含锌指和BTB结构域18（ZBTB18/ZNF238/RP58）是一种锌指转录抑制因子，在脑发育和神经元分化中起关键作用。在这里，ZBTB18在GBM的间充质亚型中主要通过异常的启动子甲基化而沉默。ZBTB18的缺失通过调节与预后不良相关的特征导致胶质母细胞瘤的侵袭性表型。恢复ZBTB18的表达可逆转表型并损害肿瘤形成能力。这些结果表明，ZBTB18通过调节与表型侵袭性相关的基因在GBM中发挥肿瘤抑制作用。本研究描述了假定的肿瘤抑制因子ZBTB18的作用及其通过启动子高甲基化的调控，这似乎是在GBM的间充质亚型中使ZBTB18沉默的常见机制，并为特异性靶向该肿瘤亚类提供了新的机制机会。
