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Flotillin-1 palmitoylation turnover by APT-1 and ZDHHC-19 promotes cervical cancer progression by suppressing IGF-1 receptor desensitization and proteostasis

Cancer Gene Therapy volume 30, pages 302–312 (2023)Cite this article

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Abstract

We have shown that insulin-like growth factor-1 (IGF-1) induces palmitoylation turnover of Flotillin-1 (Flot-1) in the plasma membrane (PM) for cell proliferation, after IGF-1 receptor (IGF-1R) signaling activation. However, the enzymes responsible for the turnover have not been identified. Herein, we show that acyl protein thioesterases-1 (APT-1) catalyzes Flot-1 depalmitoylation, and zinc finger DHHC domain-containing protein palmitoyltransferase-19 (ZDHHC-19) repalmitoylation of the depalmitoylated Flot-1 for the turnover in cervical cancer cells. The turnover prevented desensitization of IGF-1R via endocytosis and lysosomal degradation, thereby exerting excessive IGF-1R activation in cervical cancer cells. FLOT1, LYPLA1 and ZDHHC19 were highly expressed, and epithelial-to-mesenchymal transition (EMT)-inducing TIAM1 and GREM1 coordinately upregulated in malignant cervical cancer tissues. And blocking the turnover suppressed the EMT, migration, and invasion of cervical cancer cells. Our study identifies the specific enzymes regulating Flot-1 palmitoylation turnover, and reveals a novel regulatory mechanism of IGF-1-mediated cervical cancer progression.

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Fig. 1: IGF-1-induced Flot-1 depalmitoylation by APT for Flot-1 palmitoylation turnover.
Fig. 2: Upregulation of LYPLA1 and FLOT1 in the metastatic cervical cancer.
Fig. 3: APT-1-catalyzed depalmitoylation of Flot-1 for IGF-1-induced palmitoylation turnover.
Fig. 4: Repalmitoylation of Flot-1 by ZDHHC-19 for IGF-1-induced Flot-1 palmitoylation turnover.
Fig. 5: Regulation of IGF-1R endocytosis and degradation by APT-1 and ZDHHC-19-triggered Flot-1 palmitoylation turnover.
Fig. 6: Flot-1 palmitoylation turnover promotes EMT, migration, and invasion of cervical cancer cells.

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Data availability

All data generated or analysed during this study are included in this published article and its supplementary information files.

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Acknowledgements

This work was supported by grants from the National Research Foundation of Korea NRF-2018R1D1A1B07045995 to Y.P., NRF-2018R1C1B6006816 and NRF-2021R1C1C2008110 to H.K., NRF-2020R1A6A3A13071911 and NRF-2020R1A6A1A03044344 to M.C., and NRF-2013H1A2A1034489 to D.J., and the National R&D Program for Cancer Control, Ministry of Health and Welfare, Republic of Korea (1631090 to H.K.). M.C. and Y.A. have been supported by scholarship from the BK21 Plus Program.

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  1. These authors contributed equally: Hayeong Kwon, Moonjeong Choi, Yujin Ahn.

Authors and Affiliations

  1. Division of Life Science, Graduate School of Applied Life Science (BK21 Plus Program), PMBBRC, Gyeongsang National University, Jinju, 52828, Korea

    Hayeong Kwon, Moonjeong Choi, Yujin Ahn, Donghwan Jang & Yunbae Pak

  2. Clinical Research Center, Masan National Tuberculosis Hospital, Changwon, 51755, Korea

    Donghwan Jang

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H.K., M.C., Y.A., and D.J. performed experiments. H.K. and Y.P. analyzed and interpreted the data. Y.P. conceived. H.K. and Y.P. designed the experiments. H.K. and Y.P. wrote the manuscript. All authors have read and approved the final version of the manuscript.

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Kwon, H., Choi, M., Ahn, Y. et al. Flotillin-1 palmitoylation turnover by APT-1 and ZDHHC-19 promotes cervical cancer progression by suppressing IGF-1 receptor desensitization and proteostasis. Cancer Gene Ther 30, 302–312 (2023). https://doi.org/10.1038/s41417-022-00546-2

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