International journal of biological macromolecules · 2025
Demethylase, ALKBH1, regulates osteosarcoma chemosensitivity through FZD8/Wnt/β-catenin signaling pathway in the m7G manner.
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Li Xiangyao, Lin Zili, Liu Qing, Yuan Yuhao, Luo Hao, Zheng Haibin, Luo Wei
Аннотация
BACKGROUND: The escalating chemoresistance in osteosarcoma (OS) has impeded therapeutic advancements, underscoring the critical need to elucidate the mechanisms driving OS progression. Epigenetic alterations have been implicated in the pathogenesis and progression of various cancers, including OS, suggesting that targeting these modifications could advance cancer research and therapeutic strategies.
METHODS: The roles of ALKBH1, a demethylase, in OS were explored using bioinformatics and in-vitro and in-vivo experiments. Additionally, transcriptome sequencing and RIP sequencing were performed to explore the anti-OS mechanism of ALKBH1, and rescue assays, RIP-qPCR, and m7G-MeRIP-qPCR were conducted to validate the intricate relation between ALKBH1, FZD8, Wnt/β-catenin signaling pathway, and OS chemosensitivity.
RESULTS: The present study revealed that ALKBH1 served as a tumor suppressor by promoting apoptosis, inhibiting proliferation, and suppressing metastasis in OS. Notably, ALKBH1 overexpression significantly enhanced the chemosensitivity of OS to doxorubicin. Furthermore, we demonstrated that ALKBH1 regulated the FZD8/β-catenin signaling pathway through m7G methylation, thereby suppressing OS progression both in vitro and in vivo.
CONCLUSION: This study identified ALKBH1 as a promising therapeutic target, particularly for overcoming OS chemoresistance. The ALKBH1/FZD8/β-catenin axis and its associated m7G methylation mechanisms may offer novel avenues for OS researches and treatments.
METHODS: The roles of ALKBH1, a demethylase, in OS were explored using bioinformatics and in-vitro and in-vivo experiments. Additionally, transcriptome sequencing and RIP sequencing were performed to explore the anti-OS mechanism of ALKBH1, and rescue assays, RIP-qPCR, and m7G-MeRIP-qPCR were conducted to validate the intricate relation between ALKBH1, FZD8, Wnt/β-catenin signaling pathway, and OS chemosensitivity.
RESULTS: The present study revealed that ALKBH1 served as a tumor suppressor by promoting apoptosis, inhibiting proliferation, and suppressing metastasis in OS. Notably, ALKBH1 overexpression significantly enhanced the chemosensitivity of OS to doxorubicin. Furthermore, we demonstrated that ALKBH1 regulated the FZD8/β-catenin signaling pathway through m7G methylation, thereby suppressing OS progression both in vitro and in vivo.
CONCLUSION: This study identified ALKBH1 as a promising therapeutic target, particularly for overcoming OS chemoresistance. The ALKBH1/FZD8/β-catenin axis and its associated m7G methylation mechanisms may offer novel avenues for OS researches and treatments.