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ALKBH5 inhibits thyroid cancer progression by promoting ferroptosis through TIAM1–Nrf2/HO-1 axis

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Abstract

As a critical catalytic subunit of N6-methyladenosine (m6A) modification in messenger RNA, ALKBH5 has been reported to affect the progression of numerous tumors. However, the functions and mechanisms of ALKBH5 in thyroid cancer remain largely unknown. Relative mRNA and protein levels in thyroid cancer tissues and cells were detected by qRT-PCR and western blot, respectively. The proliferation and viability were evaluated using colony formation and CCK-8 assays. Intracellular iron level was measured by an iron colorimetric assay kit. ROS level was determined using CellRox Green reagent. TIAM1 mRNA m6A level was detected by MeRIP. Xenograft tumor growth was performed to examine the role of ALKBH5 in thyroid tumor growth in vivo. ALKBH5 was decreased in thyroid cancer tissues and cells. ALKBH5 overexpression inhibited thyroid cancer cell proliferation and increased the levels of Fe2+ and ROS and reduced the proteins expression of GPX4 and SLC7A11. Furthermore, overexpression of ALKBH5 inhibited TIAM1 expression by m6A modification, and overexpression of TIAM1 reversed the regulatory of oe-ALKBH5 on cell proliferation and ferroptosis in thyroid cancer. In addition, TIAM1 was elevated in thyroid cancer, and TIAM1 knockdown repressed thyroid cancer cell proliferation and promoted ferroptosis through regulating Nrf2/HO-1 axis. In addition, in vivo evidences also showed that ALKBH5 suppressed thyroid cancer progression by decreasing the m6A level of TIAM1. Our findings suggested that ALKBH5 inhibited thyroid cancer progression by inducing ferroptosis through m6A-TIAM1–Nrf2/HO-1 axis, suggesting ALKBH5 might be a potential target molecule for the treatment and diagnosis of thyroid cancer.

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Acknowledgements

We would like to give our sincere gratitude to the reviewers for their constructive comments.

Funding

This work was supported by the National Natural Science Foundation of China (81873730), the Guiding Project of Clinical Medical Technology Innovation in Hunan Province (2020SK51706), Clinical Research Center for Breast & Thyroid Disease Prevention in Hunan Province (2018SK4001), and General Guidance Project of Hunan Provincial Health Commission (202204013843).

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Authors and Affiliations

  1. Department of Surgery, The Second Affiliated Hospital of Soochow University, No. 1055, San-Xiang Road, Suzhou, 215004, Jiangsu, People’s Republic of China

    Wei Li, Jinrong Wei & Guoqin Jiang

  2. Department of Breast and Thyroid Surgery, The Second Affiliated Hospital, Hengyang Medical College, University of South China, Hengyang, 421001, Hunan, People’s Republic of China

    Wei Li & Hong Cao

  3. Hengyang Medical College, University of South China, Hengyang, 421001, Hunan, People’s Republic of China

    Guo Huang

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  1. Wei Li
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Correspondence to Guoqin Jiang.

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Human thyroid cancer tissue specimens were obtained from the Second Affiliated Hospital of Soochow University. Our study was approved by the Ethics Committee of the Second Affiliated Hospital of Soochow University. Animal procedures complied with the guidelines of the Committee on the Ethics of Animal Experiments of the Second Affiliated Hospital of Soochow University.

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Fig. S1 qRT-PCR analysis of the expression of different m6A modifying enzymes in thyroid cancer tissues. (A) qRT-PCR detected the expression of METTL14. (B) METTL3 expression was tested by qRT-PCR. (C) RBM15 expression was measured by qRT-PCR. (D) FTO expression was tested by qRT-PCR. (E) WTAP level was detected by qRT-PCR.

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Li, W., Huang, G., Wei, J. et al. ALKBH5 inhibits thyroid cancer progression by promoting ferroptosis through TIAM1–Nrf2/HO-1 axis. Mol Cell Biochem 478, 729–741 (2023). https://doi.org/10.1007/s11010-022-04541-x

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