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Published on: June 9, 2023
SUN2 downregulation promotes breast cancer cell proliferation via NFATC4 upregulation
Jaehyeok Lee1, Haein Kim1, Mirae Yeo1
1Department of Biological Sciences, Ulsan National Institute of Science and Technology (UNIST), Ulsan, 44919, Republic of Korea.
Abstract:
The linker of nucleoskeleton and cytoskeleton (LINC) complex component Sad1/UNC-84 domain-containing protein 2 (SUN2) is essential for maintaining nuclear envelope integrity and mechanical signaling between the cytoskeleton and the nucleus. However, its functional significance in breast cancer remains unclear. Here, we show that SUN2 expression is markedly reduced in breast cancer tissues and cell lines compared with normal mammary epithelial cells, and that low SUN2 levels correlate with poor overall survival in breast cancer patients. Functional studies revealed that SUN2 depletion significantly enhanced cell proliferation and colony formation, whereas SUN2 overexpression suppressed these phenotypes. Consistently, SUN2 depletion accelerated xenograft tumor growth and increased Ki-67 positivity, confirming enhanced proliferative activity in vivo. Transcriptomic profiling identified nuclear factor of activated T cells, cytoplasmic 4 (NFATC4), a Ca2+/calcineurin-responsive transcription factor, as one of the most strongly upregulated gene following SUN2 loss. Analysis of TCGA-BRCA data further revealed a significant inverse correlation between SUN2 and NFATC4 expression. Mechanistically, SUN2 depletion elevated NFATC4 mRNA and protein levels, while SUN2 overexpression reduced them. NFATC4 overexpression promoted proliferation, whereas co-expression of SUN2 attenuated NFATC4 expression and reversed its growth-promoting effects. Together, these findings reveal a previously unrecognized SUN2-NFATC4 regulatory axis and establish SUN2 as a tumor-suppressive component of the LINC complex in breast cancer.
Insights
Sad1/UNC-84 domain-containing protein 2 (SUN2) acts as a tumor suppressor in breast cancer. Reduced SUN2 expression promotes cancer cell proliferation and tumor growth by upregulating nuclear factor of activated T cells, cytoplasmic 4 (NFATC4).
Area of Science:
- Cell Biology
- Molecular Oncology
- Cancer Research
Background:
- The linker of nucleoskeleton and cytoskeleton (LINC) complex is crucial for nuclear envelope integrity and mechanical signaling.
- Sad1/UNC-84 domain-containing protein 2 (SUN2), a LINC complex component, has an unclear role in breast cancer pathogenesis.
- Understanding SUN2's function is vital for identifying new therapeutic targets in breast cancer.
Purpose of the Study:
- To investigate the functional significance of SUN2 in breast cancer.
- To elucidate the molecular mechanisms underlying SUN2's role in breast cancer progression.
- To establish SUN2 as a potential tumor suppressor in breast cancer.
Main Methods:
- Analysis of SUN2 expression in breast cancer tissues and cell lines.
- Functional studies including SUN2 depletion and overexpression in vitro and in vivo.
- Transcriptomic profiling and analysis of The Cancer Genome Atlas (TCGA-BRCA) data.
- Investigation of the regulatory relationship between SUN2 and nuclear factor of activated T cells, cytoplasmic 4 (NFATC4).
Main Results:
- SUN2 expression is significantly reduced in breast cancer, correlating with poor patient survival.
- SUN2 depletion enhances breast cancer cell proliferation, colony formation, and xenograft tumor growth.
- SUN2 loss leads to upregulation of NFATC4, a key driver of proliferation.
- SUN2 overexpression suppresses proliferation and attenuates NFATC4 levels.
Conclusions:
- SUN2 acts as a tumor suppressor in breast cancer.
- A novel SUN2-NFATC4 regulatory axis controls breast cancer cell proliferation.
- Targeting SUN2 or its downstream effectors may offer therapeutic strategies for breast cancer.
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