Abstract
Retinoic acid-related orphan receptor α (RORα) regulates diverse physiological processes, including inflammatory responses, lipid metabolism, circadian rhythm, and cancer biology. RORα 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 RORα isoform makes biochemical studies on each RORα isoform remain unclear. Here, we generate RORα2-specific antibody and characterize the role of RORα2 in promoting tumor progression in breast cancer. RORα2 requires lysine specific demethylase 1 (LSD1/KDM1A) as a coactivator for transcriptional activation of RORα2 target genes, exemplified by CTNND1. Intriguingly, RORα2 and LSD1 protein levels are dramatically elevated in human breast cancer specimens compared to normal counterparts. Taken together, our studies indicate that LSD1-mediated RORα2 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 RORα2 transcriptional activity may be potent therapeutic strategy to attenuate tumor cell migration in human breast cancer.
Highlights
receptor α (RORα), a member of the orphan nuclear receptor family, plays various roles in signal integration including modulation of homeostasis and disease by positively or negatively regulating subsets of gene expression[1]
We generated a specific antibody against the N-terminal domain (NTD) of RORα2 (Fig. 1C, left panel) and confirmed no cross-reactivity of RORα2-specific antibody with other known RORα isoforms by immunoblot analysis (Fig. 1C, right panel)
Using RORα2-specific antibody, we examined if RORα2 associates with LSD1 in HEK293 cells
Summary
RORα, a member of the orphan nuclear receptor family, plays various roles in signal integration including modulation of homeostasis and disease by positively or negatively regulating subsets of gene expression[1]. We have reported tumor suppressive function of RORα, demonstrating that RORα attenuates Wnt/β-catenin signaling by PKCα-dependent phosphorylation in colon cancer cells and that RORα enhances p53-dependent apoptotic function to inhibit tumor progression[2,19]. We report that RORα2 is critical to promote cell proliferation and migration in human breast cancer cells. RORα2 requires LSD1 as a coactivator for transcriptional activation of target genes. Using specific antibody against RORα2, we show that both RORα2 and LSD1 protein levels are elevated in breast cancer tissue specimens compared to the matched normal tissue specimens. Our data indicate that RORα2 requires LSD1 to enhance cell migration and tumor progression in human breast cancer
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