Abstract
Secondary resistance to imatinib (IM) represents a major challenge for therapy of gastrointestinal stromal tumors (GISTs). Aberrations in oncogenic pathways, including autophagy, correlate with IM resistance. Regulation of autophagy-related protein 5 (ATG5) by the ubiquitin-proteasome system is critical for autophagic activity, although the molecular mechanisms that underpin reversible deubiquitination of ATG5 have not been deciphered fully. Here, we identified USP13 as an essential deubiquitinase that stabilizes ATG5 in a process that depends on the PAK1 serine/threonine-protein kinase and which enhances autophagy and promotes IM resistance in GIST cells. USP13 preferentially is induced in GIST cells by IM and interacts with ATG5, which leads to stabilization of ATG5 through deubiquitination. Activation of PAK1 promoted phosphorylation of ATG5 thereby enhancing the interaction of ATG5 with USP13. Furthermore, N6-methyladenosine methyltransferase-like 3 (METTL3) mediated stabilization of USP13 mRNA that required the m6A reader IGF2BP2. Moreover, an inhibitor of USP13 caused ATG5 decay and co-administration of this inhibitor with 3-methyladenine boosted treatment efficacy of IM in murine xenograft models derived from GIST cells. Our findings highlight USP13 as an essential regulator of autophagy and IM resistance in GIST cells and reveal USP13 as a novel potential therapeutic target for GIST treatment.
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Acknowledgements
We would like to give our special thanks to Jin Xu for his support in Statistical analysis and Shuxian Dai for her stimulating discussions. This work was supported by grants from National Natural Science Foundation of China (grant number: 82072708); Youth Program of National Natural Science Foundation of China (grant number: 81902461); Natural Science Foundation of Province (grant number: BK20191495, BK20191073); The Priority Academic Program Development of Jiangsu Higher Education Institutions (grant number: PAPD, JX10231801); Jiangsu Key Medical Discipline (General Surgery) (grant number: ZDXKA2016005).
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Conception and design: ZSG; Data acquisition, analysis, and interpretation: CL, HX, ZKX; Investigation: YBB, ZWC, NFW, ZJW, YY, ZHL, ZYH, and BWL; Acquisition of patient specimens: FYL, ZL, LJW, ZKX and LY; Paper drafting and revising: ZSG, HX, and CL; and paper writing: ZSG. All authors approved the final version of the paper.
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Gao, Z., Li, C., Sun, H. et al. N6-methyladenosine-modified USP13 induces pro-survival autophagy and imatinib resistance via regulating the stabilization of autophagy-related protein 5 in gastrointestinal stromal tumors. Cell Death Differ 30, 544–559 (2023). https://doi.org/10.1038/s41418-022-01107-8
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DOI: https://doi.org/10.1038/s41418-022-01107-8
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