Abstract
Breast cancer that is accompanied by a high level of cyclin E expression usually exhibits poor prognosis and clinical outcome. Several factors are known to regulate the level of cyclin E during the cell cycle progression. The transcription factor DEC1 (also known as STRA13 and SHARP2) plays an important role in cell proliferation and apoptosis. Nevertheless, the mechanism of its role in cell proliferation is poorly understood. In this study, using the breast cancer cell lines MCF-7 and T47D, we showed that DEC1 could inhibit the cell cycle progression of breast cancer cells independently of its transcriptional activity. The cell cycle-dependent timing of DEC1 overexpression could affect the progression of the cell cycle through regulating the level of cyclin E protein. DEC1 stabilized cyclin E at the protein level by interacting with cyclin E. Overexpression of DEC1 repressed the interaction between cyclin E and its E3 ligase Fbw7α, consequently reducing the level of polyunbiquitinated cyclin E and increased the accumulation of non-ubiquitinated cyclin E. Furthermore, DEC1 also promoted the nuclear accumulation of Cdk2 and the formation of cyclin E/Cdk2 complex, as well as upregulating the activity of the cyclin E/Cdk2 complex, which inhibited the subsequent association of cyclin A with Cdk2. This had the effect of prolonging the S phase and suppressing the growth of breast cancers in a mouse xenograft model. These events probably constitute the essential steps in DEC1-regulated cell proliferation, thus opening up the possibility of a protein-based molecular strategy for eliminating cancer cells that manifest a high-level expression of cyclin E.
Highlights
Dependent manner, causing cell growth arrest, as well as demonstrating that DEC1 is a target of the p53 family and mediates cell cycle arrest and DNA damage-induced premature senescence.[6,7,8] DEC1 plays a role in cell survival
In order to study the function of DEC1 in breast cancer cells, we examined the expression and subcellular location of DEC1 in breast carcinoma and adjacent normal breast tissue using immunohistochemistry analysis
We found in this study that DEC1 could affect the level of cyclin E in a cell, not through its transcriptional activity (Figures 2b and c; Supplementary Figures S2A and D), but through protein-protein interaction, and this effectively allowed DEC1 to regulate the cell cycle progression, resulting in the regulation of cell proliferation
Summary
Dependent manner, causing cell growth arrest, as well as demonstrating that DEC1 is a target of the p53 family and mediates cell cycle arrest and DNA damage-induced premature senescence.[6,7,8] DEC1 plays a role in cell survival It mediates TGF-β-induced cell survival in breast cancer cells,[9] and DEC1-overexpressing cells can resist oxidative stress-mediated cell death.[10] DEC1 regulates p53-dependent cell survival versus cell death through MIC-1 in response to DNA damage stress.[11] DEC1 has multifaceted roles in cancer progression. DEC1 promoted the activity and the formation of cyclin E/Cdk[2] complex as well as the localization of cyclin E and Cdk[2] in the nucleus, and repressed the subsequent formation of the cyclin A/Cdk[2] complex, which led to the cells stalling at the S phase These findings provided new insight into the mechanism associated with DEC1-regulated cell cycle and proliferation of breast cancer cells
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