Epinephrine promotes breast cancer metastasis through a ubiquitin-specific peptidase 22–mediated lipolysis circuit
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 <i>Atgl</i> 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.
Authors
- Zhaolin Sun (ORCID: https://orcid.org/0009-0003-0180-3286)
- Peng Chu (ORCID: https://orcid.org/0000-0002-5371-3018)
- Janice Lu (ORCID: https://orcid.org/0009-0006-8926-6367)
- Deyu Fang (ORCID: https://orcid.org/0000-0002-4211-2751)
- Chen Su (ORCID: https://orcid.org/0009-0005-6018-8441)
- Juncheng Wei (ORCID: https://orcid.org/0000-0001-5262-477X)
- Huijun Jia (ORCID: https://orcid.org/0000-0003-3463-1575)
- Suxian Ma (ORCID: https://orcid.org/0009-0009-7335-3716)
- Yu-Qiao Pang
- Guoqing Xue (ORCID: https://orcid.org/0000-0002-1888-4276)
- Yuanzhang Zhou (ORCID: https://orcid.org/0000-0002-9806-9254)
- Zhuoyue Zhao (ORCID: https://orcid.org/0009-0001-7459-1726)
- Qiong Gao (ORCID: https://orcid.org/0009-0002-8416-6026)
- Hui Zhang (ORCID: https://orcid.org/0000-0001-6825-5649)
- Ya Wang (ORCID: https://orcid.org/0000-0001-6229-4495)
- Shengnan Wang (ORCID: https://orcid.org/0000-0001-8551-8164)
- Jian Wang (ORCID: https://orcid.org/0000-0002-8116-7691)
- Jiankun Song (ORCID: https://orcid.org/0009-0008-0830-1832)
- Na Li (ORCID: https://orcid.org/0009-0002-3469-5579)
- Yue Zhao (ORCID: https://orcid.org/0009-0006-8886-4314)
- Hongjiang Wang (ORCID: https://orcid.org/0000-0002-1060-1737)
- Jia Sun (ORCID: https://orcid.org/0009-0003-3234-2128)
- Bingjin Hu (ORCID: https://orcid.org/0009-0006-1645-1430)
- Houyu Zhu (ORCID: https://orcid.org/0009-0001-8548-7895)
- Yue Zhang (ORCID: https://orcid.org/0009-0006-4758-4359)
Institutions
- Northwestern University (US)
- Dalian Medical University (CN)
- Dalian Municipal Central Hospital (CN)
- First Affiliated Hospital of Dalian Medical University (CN)
- Beijing Proteome Research Center (CN)
- Robert H. Lurie Comprehensive Cancer Center of Northwestern University
Publication Details
- Journal
- Science Advances
- Published
- 2024-08-16
- DOI
- https://doi.org/10.1126/sciadv.ado1533
- Citations
- 17
- Primary Topic
- Sirtuins and Resveratrol in Medicine
- Type
- article
- Field-Weighted Citation Impact
- 5.85
Funders
- Northwestern University
- Robert H. Lurie Comprehensive Cancer Center