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Macrophage Differentiation and Polarization into an M2-Like Phenotype using a Human Monocyte-Like THP-1 Leukemia Cell Line
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TRIM21-mediated Sohlh2 ubiquitination suppresses M2 macrophage polarization and progression of triple-negative breast

Ruihong Zhang1, Ying Shen1, Qi Zhang1

  • 1Key Laboratory of The Ministry of Education for Experimental Teratology, Department of Histology and Embryology, School of Basic Medical Sciences, Cheeloo College of Medicine, Shandong University, 44 Wenhua Xi Road, Jinan, Shandong, 250012, China.

Cell Death & Disease
|December 20, 2023
PubMed

Insights

Sohlh2 in macrophages promotes triple-negative breast cancer (TNBC) lung metastasis by enhancing M2 polarization. Targeting Sohlh2 offers a new therapeutic strategy for TNBC.

Area of Science:

  • Oncology
  • Immunology
  • Molecular Biology

Background:

  • Triple-negative breast cancer (TNBC) lung metastasis is a primary cause of mortality.
  • Tumor-associated macrophages (TAMs), particularly M2-like phenotypes, exhibit immunosuppressive activity and promote TNBC progression.
  • The role of the transcription factor Sohlh2 in macrophage polarization and TNBC metastasis is not well understood.

Purpose of the Study:

  • To investigate the role of Sohlh2 in macrophage polarization.
  • To determine the impact of Sohlh2 in M2-like macrophages on TNBC cell growth, migration, and lung metastasis.
  • To elucidate the molecular mechanisms underlying Sohlh2's function in TNBC progression.

Main Methods:

  • Overexpression of Sohlh2 in macrophages.
  • In vitro and in vivo assays to assess TNBC cell growth, migration, and metastasis.
  • Analysis of LXRα, ABCA1, and ABCG1 expression.
  • Chromatin immunoprecipitation to assess Sohlh2 binding to the LXRα promoter.
  • Investigation of TRIM21-mediated Sohlh2 ubiquitination and degradation.

Main Results:

  • Sohlh2 overexpression promoted M2 macrophage polarization.
  • High Sohlh2 expression in M2-like macrophages enhanced TNBC cell growth, migration, and lung metastasis.
  • Sohlh2 up-regulated LXRα, ABCA1, and ABCG1 expression, disrupting macrophage lipid homeostasis.
  • Sohlh2 directly bound to and activated the LXRα promoter.
  • TRIM21-mediated degradation of Sohlh2 suppressed M2 polarization and TNBC progression.

Conclusions:

  • Sohlh2 in macrophages drives M2 polarization and promotes TNBC lung metastasis.
  • The Sohlh2-LXRα pathway is crucial for macrophage-mediated pro-tumor effects in TNBC.
  • TRIM21 acts as a negative regulator of Sohlh2, inhibiting M2 polarization and TNBC progression.
  • Sohlh2 in macrophages represents a potential therapeutic target for inhibiting TNBC metastasis.

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