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

Abstract

HOXC10is a critical player in the development of spinal cord, formation of neurons, and associated with human leukemia. We found thatHOXC10is overexpressed in breast cancer and transcriptionally regulated by estrogen (17β-estradiol, E2). TheHOXC10promoter contains several estrogen response elements (ERE1–7, half-sites). A luciferase-based reporter assay showed that ERE1 and ERE6 ofHOXC10promoter are E2responsive. ERα and ERβ play critical roles in E2-mediated activation ofHOXC10. Knockdown of ERα and ERβ downregulated E2-inducedHOXC10expression. ERα and ERβ bind to ERE1 and ERE6 regions in an E2-dependent manner. Additionally, knockdown of histone methylasesMLL3andMLL4(but notMLL1andMLL2) diminished E2-induced expression ofHOXC10. MLL3 and MLL4 were bound to the ERE1 and ERE6 regions ofHOXC10promoter in an E2-dependent manner. Overall, we demonstrated thatHOXC10is overexpressed in breast cancer, and it is an E2-responsive gene. Histone methylases MLL3 and MLL4, along with ERs, regulateHOXC10gene expression in the presence of E2.