TRIM21-mediated Sohlh2 ubiquitination suppresses M2 macrophage polarization and progression of triple-negative breast cancer

Lung metastasis is the major cause of death in patients with triple-negative breast cancer (TNBC). Tumor-associated macrophages (TAMs) represent the M2-like phenotype with potent immunosuppressive activity, and play a pro-tumor role in TNBC lung metastasis. Sohlh2 belongs to the basic helix-loop-hel...

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Bibliographic Details
Published in:Cell death & disease 2023-12, Vol.14 (12), p.850-850, Article 850
Main Authors: Zhang, Ruihong, Shen, Ying, Zhang, Qi, Feng, Xiaoning, Liu, Xuyue, Huo, Xiaoning, Sun, Jinhao, Hao, Jing
Format: Article
Language:English
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ABCA1 protein
Antibodies
ATP-binding protein
Biochemistry
Biomedical and Life Sciences
Breast cancer
Cell Biology
Cell Culture
Cell Line, Tumor
Helix-loop-helix proteins (basic)
Homeostasis
Humans
Immunology
Immunosuppressive agents
Leukocyte migration
Life Sciences
Lung cancer
Lung Neoplasms - genetics
Macrophages
Macrophages - metabolism
Metastases
Metastasis
Phenotypes
Polarization
Signal Transduction
Therapeutic targets
Triple Negative Breast Neoplasms - pathology
Tumor Microenvironment
Tumors
Ubiquitin-protein ligase
Ubiquitination
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Summary:Lung metastasis is the major cause of death in patients with triple-negative breast cancer (TNBC). Tumor-associated macrophages (TAMs) represent the M2-like phenotype with potent immunosuppressive activity, and play a pro-tumor role in TNBC lung metastasis. Sohlh2 belongs to the basic helix-loop-helix transcription factor family. However, its role in macrophages polarization remains unknown, especially in TNBC progression. Here we demonstrated that Sohlh2 overexpression promoted M2 macrophage polarization. Moreover, high expression of Sohlh2 in M2-like macrophage enhanced TNBC cell growth, migration and lung metastasis in vivo and in vitro. Mechanistically, we revealed that Sohlh2 functioned through up-regulating LXRα, ABCA1, ABCG1 expression and disturbing the lipid homeostasis on the membrane of macrophages. Sohlh2 could directly bind to the promoter of LXRα and promote its transcription activity. E3 ubiquitin ligase TRIM21 promoted Sohlh2 ubiquitination and degradation, and suppressed M2 macrophage polarization and TNBC progression. Collectively, our findings suggested that Sohlh2 in macrophage could be a novel therapeutic target for TNBC metastatic treatment.
ISSN:2041-4889
2041-4889
DOI:10.1038/s41419-023-06383-x