期刊
CELLS
卷 8, 期 8, 页码 -出版社
MDPI
DOI: 10.3390/cells8080930
关键词
breast cancer; c-Src; EGFR; HDAC3; pY-HDAC3Y328; 331 antibody
类别
资金
- National Research Foundation of Korea (NRF) MRC - Korean government (MSIT) [2018R1A5A2020732]
- Basic Science Program through the National Research Foundation of Korea (NRF) - Ministry of Science and ICT [NRF-2017R1C1B2005993]
- Main Research Program of the Korea Food Research Institute (KFRI) - Ministry of Science and ICT [E-0150301]
Breast cancer is one of the leading causes of morbidity and mortality among women. Epidermal growth factor receptor (EGFR) and proto-oncogene tyrosine-protein kinase Src (c-Src) are critical components of the signaling pathways that are associated with breast cancer. However, the regulatory mechanism of histone deacetylase 3 (HDAC3) in these pathways remains unclear. Using the Net Phos 3.1 program for the analysis of kinase consensus motifs, we found two c-Src-mediated putative phosphorylation sites, tyrosine (Tyr, Y)-328 and Y331 on HDAC3, and generated a phospho-specific HDAC3 antibody against these sites. c-Src-mediated phosphorylation was observed in the cells expressing wild-type HDAC3 (HDAC3(WT)), but not in cells overexpressing phosphorylation-defective HDAC3 (HDAC3(Y328/331A)). Phosphorylated HDAC3 showed relatively higher deacetylase activity, and PP2, which is a c-Src inhibitor, blocked HDAC3 phosphorylation and reduced its enzymatic activity. EGF treatment resulted in HDAC3 phosphorylation in both MDA-MB-231 and EGFR-overexpressing MCF7 (MCF7-EGFR) cells, but not in MCF7 cells. Total internal reflection fluorescence analysis showed that HDAC3 was recruited to the plasma membrane following EGF stimulation. HDAC3 inhibition with either c-Src knockdown or PP2 treatment significantly ameliorated the invasiveness of breast cancer cells. Altogether, our findings reveal an EGF signaling cascade involving EGFR, c-Src, and HDAC3 in breast cancer cells.
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