Epinephrine promotes breast cancer metastasis through a ubiquitin-specific peptidase 22-mediated lipolysis circuit

  • Sci Adv. 2024 Aug 16;10(33):eado1533. doi: 10.1126/sciadv.ado1533.
Yuanzhang Zhou  1 ,  Peng Chu  1  2 ,  Ya Wang  3 ,  Na Li  1 ,  Qiong Gao  1  4 ,  Shengnan Wang  1  4 ,  Juncheng Wei  4 ,  Guoqing Xue  1 ,  Yue Zhao  5 ,  Huijun Jia  1 ,  Jiankun Song  1 ,  Yue Zhang  3 ,  Yujie Pang  3 ,  Houyu Zhu  1 ,  Jia Sun  2 ,  Suxian Ma  2 ,  Chen Su  1 ,  Bingjin Hu  2 ,  Zhuoyue Zhao  1 ,  Hui Zhang  6 ,  Janice Lu  7 ,  Jian Wang  8 ,  Hongjiang Wang  3 ,  Zhaolin Sun  1  2 ,  Deyu Fang  4
Affiliations
  • 1. Department of Biochemistry and Molecular Biology, College of Basic Medical Science, Dalian Medical University, Dalian 116044, China.
  • 2. Dalian College of Pharmacy, Dalian Medical University, Dalian 116044, China.
  • 3. Department of Breast Surgery, First Affiliated Hospital of Dalian Medical University, Dalian 116044, China.
  • 4. Department of Pathology & Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 5. Department of Clinical Laboratory, Dalian Municipal Central Hospital, Dalian 116000, China.
  • 6. Department of Preventive Medicine, Feinberg School of Medicine, Northwestern University, Chicago, IL, USA.
  • 7. Department of Medicine & Lurie Cancer Center, Northwestern University Feinberg School of Medicine, Chicago, IL, USA.
  • 8. State Key Laboratory of Medical Proteomics, Beijing Proteome Research Center, National Center for Protein Sciences (Beijing), Beijing Institute of Lifeomics, Beijing 102206, China.
PMID: 39151008 DOI: 10.1126/sciadv.ado1533
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.

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