FANCD2 deficiency sensitizes SHH medulloblastoma to radiotherapy via ferroptosis

作者：Hong Zhou, Yanxia Wang, Yan‐Xia 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, Yan Wang, Xiu‐Wu Bian · 发表于：The Journal of Pathology · 年份：2024 · DOI：10.1002/path.6245 · 被引用次数：12 · 研究领域：Ferroptosis and cancer prognosis、Epigenetics and DNA Methylation、Cancer Genomics and Diagnostics

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 ...