2. Academic Validation
  3. Epigenetically silenced lncRNA SNAI3-AS1 promotes ferroptosis in glioma via perturbing the m6A-dependent recognition of Nrf2 mRNA mediated by SND1

Epigenetically silenced lncRNA SNAI3-AS1 promotes ferroptosis in glioma via perturbing the m6A-dependent recognition of Nrf2 mRNA mediated by SND1

  • J Exp Clin Cancer Res. 2023 May 19;42(1):127. doi: 10.1186/s13046-023-02684-3.
Jianglin Zheng # 1,  Qing Zhang # 1,  Zhen Zhao # 1,  Yue Qiu 2,  Yujie Zhou 1,  Zhipeng Wu 3,  Cheng Jiang 1,  Xuan Wang 4,  Xiaobing Jiang 5
Affiliations

Affiliations

  • 1 Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 2 Department of Otolaryngology, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China.
  • 3 Department of Neurosurgery, Weifang People's Hospital, Weifang, Shandong, China.
  • 4 Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. [email protected].
  • 5 Department of Neurosurgery, Union Hospital, Tongji Medical College, Huazhong University of Science and Technology, Wuhan, Hubei, China. [email protected].
  • # Contributed equally.
PMID: 37202791 DOI: 10.1186/s13046-023-02684-3
Abstract

Background: Ferroptosis has been linked to tumor progression and resistance to antineoplastic therapy. Long noncoding RNA (lncRNA) exerts a regulatory role in various biological processes of tumor cells, while the function and molecular mechanism of lncRNA in Ferroptosis are yet to be clarified in glioma.

Methods: Both gain-of-function and loss-of-function experiments were employed to investigate the effects of SNAI3-AS1 on the tumorigenesis and Ferroptosis susceptibility of glioma in vitro and in vivo. Bioinformatics analysis, Bisulfite sequencing PCR, RNA pull-down, RIP, MeRIP and dual-luciferase reporter assay were performed to explore the low expression mechanism of SNAI3-AS1 and the downstream mechanism of SNAI3-AS1 in Ferroptosis susceptibility of glioma.

Results: We found that Ferroptosis inducer erastin downregulates SNAI3-AS1 expression in glioma by increasing the DNA methylation level of SNAI3-AS1 promoter. SNAI3-AS1 functions as a tumor suppressor in glioma. Importantly, SNAI3-AS1 enhances the anti-tumor activity of erastin by promoting Ferroptosis both in vitro and in vivo. Mechanistically, SNAI3-AS1 competitively binds to SND1 and perturbs the m6A-dependent recognition of Nrf2 mRNA 3'UTR by SND1, thereby reducing the mRNA stability of Nrf2. Rescue experiments confirmed that SND1 overexpression and silence can rescue the gain- and loss-of-function ferroptotic phenotypes of SNAI3-AS1, respectively.

Conclusions: Our findings elucidate the effect and detailed mechanism of SNAI3-AS1/SND1/Nrf2 signalling axis in Ferroptosis, and provide a theoretical support for inducing Ferroptosis to improve glioma treatment.

Keywords

Ferroptosis; Glioma; LncRNA; Nrf2; m6A.

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