https://orcid.org/0000-0003-2059-3504
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ABSTRACT
Macroautophagy/autophagy-mediated anoikis resistance is crucial for tumor metastasis. As a key autophagy-related protein, ATG4B has been demonstrated to be a prospective anti-tumor target. However, the existing ATG4B inhibitors are still far from clinical application, especially for tumor metastasis. In this study, we identified a novel circRNA, circSPECC1, that interacted with ATG4B. CircSPECC1 facilitated liquid-liquid phase separation of ATG4B, which boosted the ubiquitination and degradation of ATG4B in gastric cancer (GC) cells. Thus, pharmacological addition of circSPECC1 may serve as an innovative approach to suppress autophagy by targeting ATG4B. Specifically, the circSPECC1 underwent significant m6A modification in GC cells and was subsequently recognized and suppressed by the m6A reader protein ELAVL1/HuR. The activation of the ELAVL1-circSPECC1-ATG4B pathway was demonstrated to mediate anoikis resistance in GC cells. Moreover, we also verified that the above pathway was closely related to metastasis in tissues from GC patients. Furthermore, we determined that the FDA-approved compound lopinavir efficiently enhanced anoikis and prevented metastasis by eliminating repression of ELAVL1 on circSPECC1. In summary, this study provides novel insights into ATG4B-mediated autophagy and introduces a viable clinical inhibitor of autophagy, which may be beneficial for the treatment of GC with metastasis.
Disclosure statement
No potential conflict of interest was reported by the author(s).
Data availability statement
All data supporting this paper are presented within the paper and/or the Supplementary Materials. The datasets generated and/or analyzed during the current study are available from the corresponding author upon reasonable request.
Abbreviations
| ATG4B | = | autophagy related 4B cysteine peptidase |
| Baf A1 | = | bafilomycin A1 |
| ECM | = | extracellular matrix |
| FDA | = | Food and Drug Administration |
| FISH | = | fluorescence in situ hybridization |
| FL | = | full length |
| GAPDH | = | glyceraldehyde-3-phosphate dehydrogenase |
| GC | = | gastric cancer |
| HRP | = | horseradish peroxidase |
| IF | = | immunofluorescence |
| IHC | = | immunohistochemistry |
| LLPS | = | liquid-liquid phase separation |
| m6A | = | N6-methyladenosine |
| MAP1LC3B/LC3B | = | microtubule associated protein 1 light chain 3 beta |
| PTMs | = | post-translational modifications |
| RBP | = | RNA-binding protein |
| RIP | = | RNA-binding protein immunoprecipitation |
| shRNA | = | short hairpin RNA |
| siRNA | = | short interfering RNA |
| SQSTM1 | = | sequestosome 1 |
Supplementary material
Supplemental data for this article can be accessed online at https://doi.org/10.1080/15548627.2024.2325304