Zhang Peisu, Lathia Justin D, Flavahan William A, Rich Jeremy N, Mattson Mark P
Laboratory of Neurosciences, National Institute on Aging Intramural Research Program, Baltimore, MD, USA.
Trends Neurosci. 2009 Nov;32(11):559-65. doi: 10.1016/j.tins.2009.07.005. Epub 2009 Sep 11.
Glioblastoma brain tumors harbor a small population of cancer stem cells that are resistant to conventional chemotherapeutic and radiation treatments, and are believed responsible for tumor recurrence and mortality. The identification of the epigenetic molecular mechanisms that control self-renewal of glioblastoma stem cells will foster development of targeted therapeutic approaches. The transcriptional repressor REST, best known for its role in controlling cell fate decisions in neural progenitor cells, may also be crucial for cancer stem cell self-renewal. Two novel mechanisms for regulating the stability of REST have recently been revealed: these involve the telomere-binding protein TRF2 and the ubiquitin E3 ligase SCFbeta-TrCP. Reduced TRF2 binding to REST, and increased SCFbeta-TrCP activity, target REST for proteasomal degradation and thereby inhibit cancer stem cell proliferation. Neurological side effects of treatments that target REST and TRF2 may be less severe than conventional brain tumor treatments because postmitotic neurons do not express REST and have relatively stable telomeres.
胶质母细胞瘤脑肿瘤中存在一小部分癌症干细胞，它们对传统化疗和放射治疗具有抗性，并且被认为是肿瘤复发和死亡的原因。确定控制胶质母细胞瘤干细胞自我更新的表观遗传分子机制将促进靶向治疗方法的发展。转录抑制因子REST，因其在控制神经祖细胞的细胞命运决定中的作用而最为人所知，它可能对癌症干细胞的自我更新也至关重要。最近揭示了两种调节REST稳定性的新机制：这些机制涉及端粒结合蛋白TRF2和泛素E3连接酶SCFβ-TrCP。TRF2与REST的结合减少以及SCFβ-TrCP活性增加，将REST靶向蛋白酶体降解，从而抑制癌症干细胞增殖。靶向REST和TRF2的治疗的神经学副作用可能比传统脑肿瘤治疗的副作用轻，因为有丝分裂后的神经元不表达REST且端粒相对稳定。
