N-Terminal Domain Mediated Regulation of RORα1 Inhibits Invasive Growth in Prostate Cancer
Su Chan Park1, Il-Geun Park2, Hyunkyung Kim3
1Department of Molecular Bioscience, College of Biomedical Sciences, Kangwon National University, Chuncheon 24341, Korea. psc4932@naver.com.
Abstract:
Four members of the retinoic acid-related orphan receptor α (RORα) family (RORα1, RORα2, RORα3 and RORα4) are transcription factors that regulate several processes including circadian rhythm, lipid metabolism, cerebellar development, immune function, and cancer. Only two isoforms, RORα1 and 4, are specifically co-expressed in the murine and human. In the present study, we identified a specific N-terminal domain (NTD) of RORα1 that potentiated the downregulation of target genes involved in tumor progression and proliferation, based on results from RORα-deficient mouse embryonic fibroblasts and prostate carcinoma tissues. The hyperactivation of proliferative target genes were observed in RORα-deficient embryonic fibroblasts, and reconstitution of RORα1 inhibited this activation by a NTD dependent manner. Downregulation of RORα1 and upregulation of Wnt/β-catenin target genes were correlated in prostate cancer patients. These findings revealed the control of invasive growth by NTD-mediated RORα1 signaling, suggesting advanced approaches for the development of therapeutic drugs.
Insights
Retinoic acid-related orphan receptor alpha 1 (RORα1) has an N-terminal domain (NTD) that suppresses tumor growth. This RORα1 NTD controls invasive growth, offering potential for new cancer therapies.
Area of Science:
- Molecular Biology
- Cancer Biology
- Endocrinology
Background:
- Retinoic acid-related orphan receptor alpha (RORα) comprises four isoforms (RORα1-4) regulating key cellular processes.
- RORα1 and RORα4 are co-expressed in human and murine tissues.
- RORα's role in cancer progression and proliferation is under investigation.
Purpose of the Study:
- To identify specific domains of RORα1 involved in regulating genes associated with tumor progression.
- To investigate the mechanism by which RORα1 influences tumor cell proliferation and invasive growth.
- To explore the correlation between RORα1 expression and Wnt/β-catenin signaling in prostate cancer.
Main Methods:
- Utilized RORα-deficient mouse embryonic fibroblasts (MEFs) to assess RORα1's function.
- Analyzed prostate carcinoma tissues to correlate RORα1 expression with cancer gene activity.
- Employed gene expression analysis to examine target genes involved in proliferation and tumor progression.
Main Results:
- A specific N-terminal domain (NTD) of RORα1 was identified to potentiate the downregulation of target genes promoting tumor progression.
- RORα-deficient MEFs exhibited hyperactivation of proliferative genes, which was inhibited by RORα1 reconstitution in a NTD-dependent manner.
- A negative correlation was observed between RORα1 expression and Wnt/β-catenin target gene upregulation in prostate cancer patients.
Conclusions:
- The NTD of RORα1 plays a critical role in suppressing tumor progression and proliferation.
- NTD-mediated RORα1 signaling effectively controls invasive growth.
- These findings suggest RORα1's NTD as a potential therapeutic target for developing novel anti-cancer drugs.
Related Concept Videos
02:26Conservation of Protein Domains Over Different Proteins
A limited set of protein domains often duplicate and recombine during evolution. These domains can be organized in different combinations to...
01:44Termination of Translation
01:44Termination of Translation
02:24Regulation of Expression Occurs at Multiple Steps
Transcription results in the generation of precursor (pre-mRNA) that consists of both exons and introns, which needs further processing before being translated to a...
00:46Feedback Inhibition
01:46Epigenetic Regulation