State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China; School of Life Science and Technology, ShanghaiTech University, Shanghai 201210, China.
State Key Laboratory of Molecular Biology, CAS Center for Excellence in Molecular Cell Science, Institute of Biochemistry and Cell Biology, Chinese Academy of Sciences, University of Chinese Academy of Sciences, Shanghai 200031, China.
Cancer Cell. 2020 Dec 14;38(6):844-856.e7. doi: 10.1016/j.ccell.2020.10.009. Epub 2020 Nov 12.
Ependymoma is the third most common pediatric tumor with posterior fossa group A (PFA) being its most aggressive subtype. Ependymomas are generally refractory to chemotherapies and thus lack any effective treatment. Here, we report that elevated expression of CXorf67 (chromosome X open reading frame 67), which frequently occurs in PFA ependymomas, suppresses homologous recombination (HR)-mediated DNA repair. Mechanistically, CXorf67 interacts with PALB2 and inhibits PALB2-BRCA2 interaction, thereby inhibiting HR repair. Concordantly, tumor cells with high CXorf67 expression levels show increased sensitivity to poly(ADP-ribose) polymerase (PARP) inhibitors, especially when combined with radiotherapy. Thus, our findings have revealed a role of CXorf67 in HR repair and suggest that combination of PARP inhibitors with radiotherapy could be an effective treatment option for PFA ependymomas.
室管膜瘤是第三大常见的儿童肿瘤，其中后颅窝组 A（PFA）是最具侵袭性的亚型。室管膜瘤通常对化疗药物有抗药性，因此缺乏有效的治疗方法。在这里，我们报告了 CXorf67（X 染色体开放阅读框 67）的表达升高，这在 PFA 室管膜瘤中经常发生，会抑制同源重组（HR）介导的 DNA 修复。在机制上，CXorf67 与 PALB2 相互作用并抑制 PALB2-BRCA2 相互作用，从而抑制 HR 修复。一致地，高表达 CXorf67 的肿瘤细胞对聚（ADP-核糖）聚合酶（PARP）抑制剂的敏感性增加，尤其是与放疗联合使用时。因此，我们的研究结果揭示了 CXorf67 在 HR 修复中的作用，并表明 PARP 抑制剂与放疗的联合应用可能是 PFA 室管膜瘤的有效治疗选择。
