2. Academic Validation
  3. Epinephrine promotes breast cancer metastasis through a ubiquitin-specific peptidase 22-mediated lipolysis circuit

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

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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