SUN2 downregulation promotes breast cancer cell proliferation via NFATC4 upregulation

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.