ROR alpha 2 requires LSD1 to enhance tumor progression in breast cancer

Abstract

Retinoic acid-related orphan receptor a (ROR alpha) regulates diverse physiological processes, including inflammatory responses, lipid metabolism, circadian rhythm, and cancer biology. ROR alpha has four different isoforms which have distinct N-terminal domains but share identical DNA binding domain and ligand binding domain in human. However, lack of specific antibody against each ROR alpha isoform makes biochemical studies on each ROR alpha isoform remain unclear. Here, we generate ROR alpha 2-specific antibody and characterize the role of ROR alpha 2 in promoting tumor progression in breast cancer. ROR alpha 2 requires lysine specific demethylase 1 (LSD1/KDM1A) as a coactivator for transcriptional activation of ROR alpha 2 target genes, exemplified by CTNND1. Intriguingly, ROR alpha 2 and LSD1 protein levels are dramatically elevated in human breast cancer specimens compared to normal counterparts. Taken together, our studies indicate that LSD1-mediated ROR alpha 2 transcriptional activity is important to promote tumor cell migration in human breast cancer as well as breast cancer cell lines. Therefore, our data establish that suppression of LSD1-mediated ROR alpha 2 transcriptional activity may be potent therapeutic strategy to attenuate tumor cell migration in human breast cancer.