Department of Cancer Biology, The University of Texas MD Anderson Cancer Center, Houston, TX 77030.
Department of Physiology, National University of Singapore, Singapore 117597, Singapore.
Proc Natl Acad Sci U S A. 2017 Oct 24;114(43):E9086-E9095. doi: 10.1073/pnas.1708122114. Epub 2017 Oct 9.
An integrated genomic and functional analysis to elucidate DNA damage signaling factors promoting self-renewal of glioma stem cells (GSCs) identified proliferating cell nuclear antigen (PCNA)-associated factor () up-regulation in glioblastoma. PAF is preferentially overexpressed in GSCs. Its depletion impairs maintenance of self-renewal without promoting differentiation and reduces tumor-initiating cell frequency. Combined transcriptomic and metabolomic analyses revealed that PAF supports GSC maintenance, in part, by influencing DNA replication and pyrimidine metabolism pathways. PAF interacts with PCNA and regulates PCNA-associated DNA translesion synthesis (TLS); consequently, PAF depletion in combination with radiation generated fewer tumorspheres compared with radiation alone. Correspondingly, pharmacological impairment of DNA replication and TLS phenocopied the effect of PAF depletion in compromising GSC self-renewal and radioresistance, providing preclinical proof of principle that combined TLS inhibition and radiation therapy may be a viable therapeutic option in the treatment of glioblastoma multiforme (GBM).
通过整合基因组和功能分析，阐明了促进神经胶质瘤干细胞（GSCs）自我更新的 DNA 损伤信号因子，鉴定出在神经母细胞瘤中增殖细胞核抗原（PCNA）相关因子（）上调。PAF 在 GSCs 中优先过表达。其耗竭会损害自我更新的维持，而不会促进分化，并降低肿瘤起始细胞频率。联合转录组学和代谢组学分析表明，PAF 通过影响 DNA 复制和嘧啶代谢途径来支持 GSC 的维持。PAF 与 PCNA 相互作用并调节 PCNA 相关的跨损伤合成（TLS）；因此，与单独放疗相比，PAF 耗竭联合放疗产生的肿瘤球更少。相应地，DNA 复制和 TLS 的药理学损伤模拟了 PAF 耗竭对 GSC 自我更新和辐射抗性的影响，为联合 TLS 抑制和放射治疗可能是治疗多形性胶质母细胞瘤（GBM）的一种可行治疗选择提供了临床前原理证明。
