HOXC10 is overexpressed in breast cancer and transcriptionally regulated by estrogen via involvement of histone methylases MLL3 and MLL4

Abstract

HOXC10 is a critical player in the development of spinal cord, formation of neurons, and associated with human leukemia. We found that HOXC10 is overexpressed in breast cancer and transcriptionally regulated by estrogen (17β-estradiol, E(2)). The HOXC10 promoter contains several estrogen response elements (ERE1-7, half-sites). A luciferase-based reporter assay showed that ERE1 and ERE6 of HOXC10 promoter are E(2) responsive. ERα and ERβ play critical roles in E(2)-mediated activation of HOXC10. Knockdown of ERα and ERβ downregulated E(2)-induced HOXC10 expression. ERα and ERβ bind to ERE1 and ERE6 regions in an E(2)-dependent manner. Additionally, knockdown of histone methylases MLL3 and MLL4 (but not MLL1 and MLL2) diminished E(2)-induced expression of HOXC10. MLL3 and MLL4 were bound to the ERE1 and ERE6 regions of HOXC10 promoter in an E(2)-dependent manner. Overall, we demonstrated that HOXC10 is overexpressed in breast cancer, and it is an E(2)-responsive gene. Histone methylases MLL3 and MLL4, along with ERs, regulate HOXC10 gene expression in the presence of E(2).