Abstract
Chronic stress-induced epinephrine (EPI) accelerates breast cancer progression and metastasis, but the molecular mechanisms remain unclear. Herein, we found a strong positive correlation between circulating EPI levels and the tumoral expression of ubiquitin-specific peptidase 22 (USP22) in patients with breast cancer. USP22 facilitated EPI-induced breast cancer progression and metastasis by enhancing adipose triglyceride lipase (ATGL)-mediated lipolysis. Targeted USP22 deletion decreased ATGL expression and lipolysis, subsequently inhibiting EPI-mediated breast cancer lung metastasis. USP22 acts as a bona fide deubiquitinase for the Atgl gene transcription factor FOXO1, and EPI architects a lipolysis signaling pathway to stabilize USP22 through AKT-mediated phosphorylation. Notably, USP22 phosphorylation levels are positively associated with EPI and with downstream pathways involving both FOXO1 and ATGL in breast cancers. Pharmacological USP22 inhibition synergized with β-blockers in treating preclinical xenograft breast cancer models. This study reveals a molecular pathway behind EPI's tumor-promoting effects and provides a strong rationale for combining USP22 inhibition with β-blockers to treat aggressive breast cancer.
| Original language | English (US) |
|---|---|
| Article number | ado1533 |
| Journal | Science Advances |
| Volume | 10 |
| Issue number | 33 |
| DOIs | |
| State | Published - Aug 2024 |
Funding
We thank the Northwestern Lurie Cancer Center flow cytometry core and genomic sequencing core for the service support. Funding: This work was supported by the National Institutes of Health (NIH) grants R01DK126908, R01DK120330, R01CA257520, and CA232347 to D.F. and the National Natural Science Foundation of China (no. 82073768) and Dalian High-level Talent Innovation Support Program (no. 2019RD03) to Z.S. Author contributions: Y. Zhou, P.C., Y.W., N.L., Q.G., S.W., G.X., Y. Zhao, H.J., J. Song, Y.P., H. Zhu, J. Sun, S.M., C.S., B.H., Z.Z., H. Zhang, J.L., and J.W. performed the studies and analyzed the data. Y. Zhao and H.W. provided patient tissue samples. H.W., Z.S., and D.F. designed the study and wrote the manuscript. Competing interests: D.F. is the inventor of a USP22-specific inhibitor and holds the US patent entitled \"Development of USP22-specific inhibitor for treatment of cancer and other human diseases\" (US63/201,330) and the cofounder of ExoMira Medicine Inc. The other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials. Acknowledgments: We thank the northwestern lurie cancer center flow cytometry core and genomic sequencing core for the service support. Funding: this work was supported by the national institutes of health (nih) grants R01dK126908, R01dK120330, R01cA257520, and cA232347 to d.F. and the national natural Science Foundation of china (no. 82073768) and dalian high-level talent innovation Support Program (no. 2019Rd03) to Z.S. Author contributions: Y. Zhou, P.c., Y.W., n.l., Q.G., S.W., G.X., Y. Zhao, h.J., J. Song, Y.P., h. Zhu, J. Sun, S.M., c.S., B.h., Z.Z., h. Zhang, J.l., and J.W. performed the studies and analyzed the data. Y. Zhao and h.W. provided patient tissue samples. h.W., Z.S., and d.F. designed the study and wrote the manuscript. Competing interests: d.F. is the inventor of a USP22-specific inhibitor and holds the US patent entitled \u201Cdevelopment of USP22-specific inhibitor for treatment of cancer and other human diseases\u201D(US63/201,330) and the cofounder of exoMira Medicine inc. the other authors declare that they have no competing interests. Data and materials availability: All data needed to evaluate the conclusions in the paper are present in the paper and/or the Supplementary Materials.
ASJC Scopus subject areas
- General
