Journal Article

DKFZ-2023-00915

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png N6-methyladenine-mediated aberrant activation of the lncRNA SOX2OT-GLI1 loop promotes non-small-cell lung cancer stemness.

Dong, H. ; Zeng, L. ; Chen, W. ; Zhang, Q. ; Wang, F. ; Wu, Y. ; Cui, B. ; Qi, J. ; Zhang, X. ; Liu, C. ; Deng, J. ; Yu, Y. ; Schmitt, C. A.DKFZ* ; Du, J.

2023
Nature Publishing Group London

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Please use a persistent id in citations: doi:10.1038/s41420-023-01442-w

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.

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Contributing Institute(s):

1. DKTK BE zentral (BE01)

Research Program(s):

1. 899 - ohne Topic (POF4-899) (POF4-899)

Appears in the scientific report 2023

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