FANCD2
基因敲除
癌症研究
范科尼贫血
音猬因子
生物
分子生物学
化学
DNA修复
细胞凋亡
细胞生物学
生物化学
信号转导
DNA
作者
Hong Zhou,Yanxia Wang,Min Wu,Chunyan Lan,Dongfang Xiang,Ruili Cai,Qinghua Ma,Jingya Miao,Xuanyu Fang,Junjie Wang,Dan Luo,Zhicheng He,You‐Hong Cui,Ping Liang,Yan Wang,Xiu‐Wu Bian
摘要
Abstract Radiotherapy is one of the standard therapeutic regimens for medulloblastoma (MB). Tumor cells utilize DNA damage repair (DDR) mechanisms to survive and develop resistance during radiotherapy. It has been found that targeting DDR sensitizes tumor cells to radiotherapy in several types of cancer, but whether and how DDR pathways are involved in the MB radiotherapy response remain to be determined. Single‐cell RNA sequencing was carried out on 38 MB tissues, followed by expression enrichment assays. Fanconi anemia group D2 gene ( FANCD2 ) expression was evaluated in MB samples and public MB databases. The function of FANCD2 in MB cells was examined using cell counting assays (CCK‐8), clone formation, lactate dehydrogenase activity, and in mouse orthotopic models. The FANCD2‐related signaling pathway was investigated using assays of peroxidation, a malondialdehyde assay, a reduced glutathione assay, and using FerroOrange to assess intracellular iron ions (Fe 2+ ). Here, we report that FANCD2 was highly expressed in the malignant sonic hedgehog (SHH) MB subtype (SHH‐MB). FANCD2 played an oncogenic role and predicted worse prognosis in SHH‐MB patients. Moreover, FANCD2 knockdown markedly suppressed viability, mobility, and growth of SHH‐MB cells and sensitized SHH‐MB cells to irradiation. Mechanistically, FANCD2 deficiency led to an accumulation of Fe 2+ due to increased divalent metal transporter 1 expression and impaired glutathione peroxidase 4 activity, which further activated ferroptosis and reduced proliferation of SHH‐MB cells. Using an orthotopic mouse model, we observed that radiotherapy combined with silencing FANCD2 significantly inhibited the growth of SHH‐MB cell‐derived tumors in vivo . Our study revealed FANCD2 as a potential therapeutic target in SHH‐MB and silencing FANCD2 could sensitize SHH‐MB cells to radiotherapy via inducing ferroptosis. © 2024 The Pathological Society of Great Britain and Ireland.
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