Retinoid orphan nuclear receptor alpha (RORα) suppresses the epithelial–mesenchymal transition (EMT) by directly repressing Snail transcription

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Abstract

Retinoid orphan nuclear receptor alpha (RORα) is a member of the orphan nuclear factor family and regulates gene expression by binding to ROR response elements (ROREs). RORα has been identified as a potential tumor suppressor; however, how downregulation of RORα promotes cancer progression is not fully understood. Here, we showed that protein levels of RORα were downregulated during the Snail-, Twist-, or transforming growth factor-β–induced epithelial–mesenchymal transition (EMT). We found that silencing of RORα induced expression of mesenchymal markers in MCF10A cells, accompanied by enhanced cell invasion, migration, and mammosphere formation. Furthermore, ectopic expression of RORα suppressed transforming growth factor-β–induced EMT processes in MCF10A and HMLE cells. These results indicate that downregulation of RORα is crucial for the induction of EMT in mammary epithelial cells. By analyzing gene expression profiles in control and RORα-expressing cells, we also identified Snail, a key regulator of EMT, as a potential target of RORα. We show that RORα expression significantly inhibits Snail transcription in breast cancer cells. Chromatin immunoprecipitation analysis demonstrated that RORα bound to the ROREs in promoter region of SNAI1 gene, and using the luciferase reporter assay, we showed that binding to the ROREs was critical for RORα to repress Snail transcription. Finally, rescue experiments substantiated that Snail mediates RORα function in suppressing EMT and mammosphere formation. These results reveal a novel function of RORα in suppressing EMT and identify Snail as a direct target of RORα in mammary epithelial cells.

Original languageEnglish
Article number102059
JournalJournal of Biological Chemistry
Volume298
Issue number7
DOIs
StatePublished - Jul 2022

Bibliographical note

Funding Information:
This study was supported by funding from the National Institutes of Health (grant nos.: 1R01CA207772 and 1R01CA215095; to R. X.) and American Cancer Society (grant no.: IRG-16-182-28; to G. X.). The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

Publisher Copyright:
© 2022 The Authors

Keywords

  • RORE
  • Snail
  • breast cancer
  • nuclear receptor
  • stemness

ASJC Scopus subject areas

  • Biochemistry
  • Molecular Biology
  • Cell Biology

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