Wang Chenyang, Xu Ningbo, Zhong Xiangyang, Liu Boyang, Tang Wenhui, He Zhenyan, Bu Xiaolu, Cao Mengyao, Zeng Huijun, Guo Hongbo
Department of Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China; Department of Geriatrics, Zhujiang Hospital, Southern Medical University, Guangzhou, Guangdong, 510282, China.
Department of Neurosurgery Center, The National Key Clinical Specialty, The Engineering Technology Research Center of Education Ministry of China on Diagnosis and Treatment of Cerebrovascular Disease, Guangdong Provincial Key Laboratory on Brain Function Repair and Regeneration, The Neurosurgery Institute of Guangdong Province, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China; Department of Interventional Therapy, Zhujiang Hospital, Southern Medical University, Guangzhou, 510282, China.
Cancer Lett. 2025 Mar 1;612:217439. doi: 10.1016/j.canlet.2025.217439. Epub 2025 Jan 4.
N-methyladenosine (m6A) methylation, is a well-known epigenetic modification involved in various biological processes, including tumorigenesis. However, the role of AlkB homolog 5 (ALKBH5), a critical component of m6A modification, remains unclear in glioma. This study investigates the function of ALKBH5 in glioma progression and its potential as a therapeutic target. We found that ALKBH5 expression was dramatically increased in glioma, and high expression of ALKBH5 predicted poor prognosis. Overexpression of ALKBH5 promotes cell proliferation, migration, and invasion in vitro and accelerates tumor growth in vivo. Furthermore, m6A-MeRIP-seq, MeRIP-qPCR, RNA pulldown, and immunoprecipitation assays revealed that the transcription factor, forkhead box protein O1 (FOXO1), was the potential target of ALKBH5. Mechanistically, ALKBH5 facilitates glioma progression by demethylating m6A-modified FOXO1 mRNA, thereby destroying FOXO1 stability and expression through a YTHDC1-dependent pathway. The downregulated FOXO1 interacts with β-catenin, increasing its nuclear accumulation and thus promoting oncogenic Wnt/β-catenin signaling. Our findings suggest that targeting the ALKBH5/FOXO1 axis may provide a novel therapeutic strategy for glioma treatment.
N-甲基腺苷（m6A）甲基化是一种众所周知的表观遗传修饰，参与包括肿瘤发生在内的各种生物学过程。然而，作为m6A修饰关键成分的烷基化修复同源蛋白5（ALKBH5）在胶质瘤中的作用仍不清楚。本研究调查了ALKBH5在胶质瘤进展中的功能及其作为治疗靶点的潜力。我们发现ALKBH5在胶质瘤中的表达显著增加，且ALKBH5高表达预示着预后不良。ALKBH5过表达促进体外细胞增殖、迁移和侵袭，并加速体内肿瘤生长。此外，m6A-甲基化RNA免疫沉淀测序、甲基化RNA免疫沉淀定量PCR、RNA下拉和免疫沉淀试验表明，转录因子叉头框蛋白O1（FOXO1）是ALKBH5的潜在靶点。机制上，ALKBH5通过去除m6A修饰的FOXO1 mRNA上的甲基促进胶质瘤进展，从而通过依赖YTHDC1的途径破坏FOXO1的稳定性和表达。下调的FOXO1与β-连环蛋白相互作用，增加其核内积累，从而促进致癌性Wnt/β-连环蛋白信号传导。我们的研究结果表明，靶向ALKBH5/FOXO1轴可能为胶质瘤治疗提供一种新的治疗策略。
