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| Item Type: | Article |
|---|---|
| Title: | N6-methyladenine-mediated aberrant activation of the lncRNA SOX2OT-GLI1 loop promotes non-small-cell lung cancer stemness |
| Creators Name: | Dong, Hongliang, Zeng, Lili, Chen, Weiwei, Zhang, Qian, Wang, Fei, Wu, Yan, Cui, Bingjie, Qi, Jingjing, Zhang, Xin, Liu, Cuilan, Deng, Jiong, Yu, Y., Schmitt, C.A. and Du, Jing |
| Abstract: | Despite the advent of precision medicine and immunotherapy, mortality due to lung cancer remains high. The sonic hedgehog (SHH) cascade and its key terminal factor, glioma-associated oncogene homolog 1 (GLI1), play a pivotal role in the stemness and drug resistance of lung cancer. Here, we investigated the molecular mechanism of non-canonical aberrant GLI1 upregulation. The SHH cascade was upregulated in stem spheres and chemo-resistant lung cancer cells and was accountable for drug resistance against multiple chemotherapy regimens. GLI1 and the long non-coding RNA SOX2OT were positively regulated, and the GLI1-SOX2OT loop mediated the proliferation of parental and stem-like lung cancer cells. Further mechanistic investigation revealed that SOX2OT facilitated METTL3/14/IGF2BP2-mediated m6A modification and stabilization of the GLI1 mRNA. Additionally, SOX2OT upregulated METTL3/14/IGF2BP2 by sponging miR-186-5p. Functional analysis corroborated that GLI1 acted as a downstream target of METTL3/14/IGF2BP2, and GLI1 silencing could block the oncogenicity of lung cancer stem-like cells. Pharmacological inhibition of the loop remarkably inhibited the oncogenesis of lung cancer cells in vivo. Compared with paired adjacent normal tissues, lung cancer specimens exhibited consistently upregulated GLI1/SOX2OT/METTL3/14/IGF2BP2. The m6A-modified GLI1-SOX2OT loop may serve as a potential therapeutic target and prognostic predictor for lung cancer therapy and diagnosis in the clinic. |
| Keywords: | Cancer Stem Cells, Long non-Coding RNAs |
| Source: | Cell Death Discovery |
| ISSN: | 2058-7716 |
| Publisher: | Nature Publishing Group |
| Volume: | 9 |
| Number: | 1 |
| Page Range: | 149 |
| Date: | 6 May 2023 |
| Official Publication: | https://doi.org/10.1038/s41420-023-01442-w |
| PubMed: | View item in PubMed |
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