RESUMO
The histone H3K9 methyltransferase SETDB2 is involved in cell cycle dysregulation in acute leukemia and has oncogenic roles in gastric cancer. In our study, we found that SETDB2 plays essential roles in breast cancer stem cell maintenance. Depleted SETDB2 significantly decreased the breast cancer stem cell population and mammosphere formation in vitro and also inhibited breast tumor initiation and growth in vivo. Restoring SETDB2 expression rescued the defect in breast cancer stem cell maintenance. A mechanistic analysis showed that SETDB2 upregulated the transcription of the ΔNp63α downstream Hedgehog pathway gene. SETDB2 also interacted with and methylated ΔNp63α, and stabilized ΔNp63α protein. Restoring ΔNp63α expression rescued the breast cancer stem cell maintenance defect which mediated by SETDB2 knockdown. In conclusion, our study reveals a novel function of SETDB2 in cancer stem cell maintenance in breast cancer.
Assuntos
Neoplasias da Mama/metabolismo , Histona-Lisina N-Metiltransferase/metabolismo , Células-Tronco Neoplásicas/metabolismo , Fatores de Transcrição/metabolismo , Proteínas Supressoras de Tumor/metabolismo , Linhagem Celular Tumoral , Cicloeximida/farmacologia , Feminino , Regulação Neoplásica da Expressão Gênica/efeitos dos fármacos , Regulação Neoplásica da Expressão Gênica/fisiologia , Proteínas Hedgehog/genética , Proteínas Hedgehog/metabolismo , Histona-Lisina N-Metiltransferase/genética , Humanos , Leupeptinas/farmacologia , Células-Tronco Neoplásicas/efeitos dos fármacos , Fatores de Transcrição/genética , Proteínas Supressoras de Tumor/genéticaRESUMO
OBJECTIVE: To explore the effect of nicotine on the autophagy level of human periodontal ligament cells (hPDLCs). METHODS: Periodontal tissues collected from premolars for orthodontic treatment reasons were used to culture hPDLCs. Western blot analysis was performed to test the most optimal time and concentration of nicotine on the autophagy level of the hPDLCs. Transmission electron microscope and immunofluorescence observation were carried out to detect the form of autophagosomes and expression of autophagy related protein LC3 in hPDLCs under this optimal condition. RESULTS: Protein expression of LC3â ¡ was up regulated with the 12 h nicotine stimulating. Besides that, the up regulation of the protein expression of LC3â ¡ was concentration dependent and nicotine with a concentration of 1×10â»5 mol·L⻹ was the most optimal condition. Transmission electron microscope and immunofluorescence observations indicated that nicotine would activate the autophagy level of hPDLCs by increasing the number of autophagosomes and up regulating the expression of autophagy related protein LC3. CONCLUSIONS: Nicotine could increase autophagy level of hPDLCs, thus affecting the occurrence and development of smoking related periodontitis.