JMJD3 regulates the M2-like macrophage polarization and promotes the growth of breast cancer cells via STAT6/IRF4 axis.

Abstract

M2-like macrophages play a critical role in breast cancer progression. Although JMJD3 is reported to play a significant role in M2-like macrophage polarization, its precise mechanism remains unclear. By using PMA, IL-4, and IL-13, we successfully induced THP-1 cells into M2-like macrophages, which subsequently promoted breast cancer cell proliferation and inhibited apoptosis, accompanied by increased JMJD3 expression. We demonstrated that JMJD3 enhances M2-like macrophage polarization: knockdown of JMJD3 decreased the M2-like macrophage gene expression, while overexpression of JMJD3 produced the opposite effects. Furthermore, JMJD3 promoted M2-like macrophage polarization through the STAT6/IRF4 axis. Knockdown of JMJD3 abrogated IL-4/IL-13 induced IRF4 expression, while overexpression of JMJD3 upregulated IRF4 expression. Inhibition of STAT6 downregulated the expression of JMJD3, IRF4, and M2-like macrophage marker genes. Additionally, inhibiting JMJD3 and STAT6 in macrophages increased cell apoptosis and decreased cell viability in breast cancer cells, while JMJD3 overexpression exhibited pro-tumor activity. In conclusion, our findings highlight the role of JMJD3 in regulating M2-like macrophage polarization and its impact on breast cancer development through the STAT6/IRF4 axis.