Expression of the SNAI2 transcriptional repressor is regulated by C16-ceramide
| Autor: | Christina Voelkel-Johnson, Rose Nganga, Mark Kester, Shai White-Gilbertson, Ping Lu |
|---|---|
| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Pharmacology Cancer Research Gene knockdown Ceramide Cell biology Small hairpin RNA 03 medical and health sciences chemistry.chemical_compound SNAI2 030104 developmental biology 0302 clinical medicine Oncology chemistry 030220 oncology & carcinogenesis SNAI1 Molecular Medicine lipids (amino acids peptides and proteins) Epithelial–mesenchymal transition Ceramide synthase Transcription factor |
| Zdroj: | Cancer Biology & Therapy. 20:922-930 |
| ISSN: | 1555-8576 1538-4047 |
| DOI: | 10.1080/15384047.2019.1579962 |
| Popis: | Ceramide synthase 6 (CerS6) is an enzyme that preferentially generates pro-apoptotic C16-ceramide in the sphingolipid metabolic pathway. Reduced expression of CerS6 has been associated with apoptosis resistance and recent studies point to a role for CerS6 in epithelial mesenchymal transition (EMT). Because cells that undergo EMT are also more resistant to apoptosis, we hypothesized that reduced expression of CerS6 could induce changes that are associated with EMT. We found that shRNA-mediated knockdown of CerS6 increases expression of the EMT transcription factor SNAI2 but not SNAI1 or TWIST. Treatment with C6-ceramide nanoliposomes (CNL) resulted in a preferential increase in C16-ceramide and suppressed SNAI2 transcriptional activation and protein expression. The increase in C16-ceramide following CNL treatment was dependent on CerS activity and occurred even when CerS6 shRNA was expressed. shRNA against CerS5, which like CerS6 preferentially generates C16-ceramide, also decreased transcriptional activation of SNAI2, suggesting a role for C16-ceramide rather than a specific enzyme in the regulation of this transcription factor. While loss of CerS6 has been associated with apoptosis resistance, we found that cells lacking this protein are more susceptible to the effects CNL. In summary, our study identifies SNAI2 as a novel target whose expression can be influenced by C16-ceramide levels. The potential of CNL to suppress SNAI2 expression has important clinical implications, since elevated expression of this transcription factor has been associated with an aggressive phenotype or poor outcomes in several types of solid tumors. |
| Databáze: | OpenAIRE |
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