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RORα2 requires LSD1 to enhance tumor progression in breast cancer
Kyeongkyu Kim1, Ji Min Lee1, Young Suk Yu1
1Creative Research Initiatives Center for Chromatin Dynamics, School of Biological Sciences, Seoul National University, Seoul, 151-742, South Korea.
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.
Insights
A new RORα2-specific antibody reveals that lysine specific demethylase 1 (LSD1) coactivates RORα2 in breast cancer. Elevated RORα2 and LSD1 promote tumor cell migration, suggesting a therapeutic target.
Area of Science:
- * Molecular biology
- * Cancer research
- * Endocrinology
Background:
- * Retinoic acid-related orphan receptor α (RORα) influences inflammation, metabolism, circadian rhythms, and cancer.
- * RORα has four isoforms with distinct N-termini but shared DNA/ligand binding domains.
- * Lack of isoform-specific antibodies hinders biochemical studies of RORα isoforms.
Purpose of the Study:
- * To generate a RORα2-specific antibody.
- * To investigate the role of RORα2 in breast cancer progression.
- * To elucidate the mechanism of RORα2-mediated transcriptional activation.
Main Methods:
- * Generation and characterization of a RORα2-specific antibody.
- * Analysis of RORα2 and LSD1 protein levels in breast cancer specimens.
- * Investigation of RORα2 and lysine specific demethylase 1 (LSD1/KDM1A) interaction and function.
Main Results:
- * A RORα2-specific antibody was successfully generated.
- * RORα2 requires LSD1 as a coactivator for target gene transcription (e.g., CTNND1).
- * RORα2 and LSD1 protein levels are significantly elevated in human breast cancer tissues.
- * LSD1-mediated RORα2 activity promotes breast cancer cell migration.
Conclusions:
- * LSD1 is a crucial coactivator for RORα2 transcriptional activity.
- * Elevated RORα2 and LSD1 levels correlate with breast cancer progression.
- * Targeting LSD1-mediated RORα2 activity presents a potential therapeutic strategy for breast cancer.