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Fe65 Suppresses Breast Cancer Cell Migration and Invasion through Tip60 Mediated Cortactin Acetylation.

Sun Y, Sun J, Lungchukiet P, Quarni W, Yang S, Zhang X, Bai W - Sci Rep (2015)

Bottom Line: The present study documents for the first time a role of Fe65 in suppressing breast cancer cell migration and invasion.Mechanistic studies suggest that the suppression is mediated through its phosphotyrosine binding domain 1 that mediates the recruitment of Tip60 to cortactin to stimulate its acetylation.The studies identify the Tip60 acetyltransferase as a cytoplasmic drug target for the therapeutic intervention of metastatic breast cancers.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pathology and Cell Biology, University of South Florida Morsani College of Medicine, Tampa, FL 33612.

ABSTRACT
Fe65 is a brain-enriched adaptor protein known for its role in the action of the Aβ amyloid precursor protein in neuronal cells and Alzheimer's disease, but little is known about its functions in cancer cells. The present study documents for the first time a role of Fe65 in suppressing breast cancer cell migration and invasion. Mechanistic studies suggest that the suppression is mediated through its phosphotyrosine binding domain 1 that mediates the recruitment of Tip60 to cortactin to stimulate its acetylation. The studies identify the Tip60 acetyltransferase as a cytoplasmic drug target for the therapeutic intervention of metastatic breast cancers.

No MeSH data available.


Related in: MedlinePlus

The effect of Fe65 on breast cancer cell motility is acetylation-sensitive.MDA-MB-231 cells were transfected with control or Fe65 siRNA. 40 h post transfections; cells were treated with DMSO, 1 μM SAHA, 2 μM tubastatin A (Tuba A) or 2 μg/ml ACY1215 for 8 h. (A), Western blot analyses were performed to show efficient Fe65 knockdown and β-actin blot was included to show even loading. (B) and (C), Cell migration (B) and invasion (C) assays were performed as in Fig. 1A and photographed 16 h after plating. Quantitative data were presented as bar graphs and data statistics performed as described in Fig. 1.
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f2: The effect of Fe65 on breast cancer cell motility is acetylation-sensitive.MDA-MB-231 cells were transfected with control or Fe65 siRNA. 40 h post transfections; cells were treated with DMSO, 1 μM SAHA, 2 μM tubastatin A (Tuba A) or 2 μg/ml ACY1215 for 8 h. (A), Western blot analyses were performed to show efficient Fe65 knockdown and β-actin blot was included to show even loading. (B) and (C), Cell migration (B) and invasion (C) assays were performed as in Fig. 1A and photographed 16 h after plating. Quantitative data were presented as bar graphs and data statistics performed as described in Fig. 1.

Mentions: HDAC6 has been reported to control F-actin-dependent cell motility by altering the acetylation status of cortactin15 and Mena is an F-actin binding protein known to regulate breast cancer invasion4344. Because Mena forms a complex with Fe65, it is thus possible that Fe65 regulates breast cancer invasion in an acetylation and HDAC6 sensitive manner. To test this, the effects of Fe65 knockdown on cell migration and invasion were examined in MDA-MB-231 cells in the presence or absence of the pan-HDAC or HDAC6-selective inhibitors. As shown in Fig. 2A, transient transfection with Fe65 siRNA significantly decreased Fe65 protein expression. Treatments with SAHA, tubastatin A or ACY1215 decreased cell migration and invasion (Fig. 2B,C, upper panels), which is consistent with the positive role of HDAC6 in cell migration and invasion documented in published studies15. Fe65 knockdown increased cell migration (Fig. 2B) and invasion (Fig. 2C) in vehicle treated cells but not in cells treated with HDAC inhibitors, indicating an acetylation and HDAC6-sensitive effect of Fe65 on cell migration and invasion. The increase in cell migration and invasion caused by Fe65 siRNA is smaller than what was detected in Fe65 stable knockdown clones (Fig. 1), possibly due to the effect of transfection reagents or the vehicle (DMSO) for HDAC inhibitors.


Fe65 Suppresses Breast Cancer Cell Migration and Invasion through Tip60 Mediated Cortactin Acetylation.

Sun Y, Sun J, Lungchukiet P, Quarni W, Yang S, Zhang X, Bai W - Sci Rep (2015)

The effect of Fe65 on breast cancer cell motility is acetylation-sensitive.MDA-MB-231 cells were transfected with control or Fe65 siRNA. 40 h post transfections; cells were treated with DMSO, 1 μM SAHA, 2 μM tubastatin A (Tuba A) or 2 μg/ml ACY1215 for 8 h. (A), Western blot analyses were performed to show efficient Fe65 knockdown and β-actin blot was included to show even loading. (B) and (C), Cell migration (B) and invasion (C) assays were performed as in Fig. 1A and photographed 16 h after plating. Quantitative data were presented as bar graphs and data statistics performed as described in Fig. 1.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4499803&req=5

f2: The effect of Fe65 on breast cancer cell motility is acetylation-sensitive.MDA-MB-231 cells were transfected with control or Fe65 siRNA. 40 h post transfections; cells were treated with DMSO, 1 μM SAHA, 2 μM tubastatin A (Tuba A) or 2 μg/ml ACY1215 for 8 h. (A), Western blot analyses were performed to show efficient Fe65 knockdown and β-actin blot was included to show even loading. (B) and (C), Cell migration (B) and invasion (C) assays were performed as in Fig. 1A and photographed 16 h after plating. Quantitative data were presented as bar graphs and data statistics performed as described in Fig. 1.
Mentions: HDAC6 has been reported to control F-actin-dependent cell motility by altering the acetylation status of cortactin15 and Mena is an F-actin binding protein known to regulate breast cancer invasion4344. Because Mena forms a complex with Fe65, it is thus possible that Fe65 regulates breast cancer invasion in an acetylation and HDAC6 sensitive manner. To test this, the effects of Fe65 knockdown on cell migration and invasion were examined in MDA-MB-231 cells in the presence or absence of the pan-HDAC or HDAC6-selective inhibitors. As shown in Fig. 2A, transient transfection with Fe65 siRNA significantly decreased Fe65 protein expression. Treatments with SAHA, tubastatin A or ACY1215 decreased cell migration and invasion (Fig. 2B,C, upper panels), which is consistent with the positive role of HDAC6 in cell migration and invasion documented in published studies15. Fe65 knockdown increased cell migration (Fig. 2B) and invasion (Fig. 2C) in vehicle treated cells but not in cells treated with HDAC inhibitors, indicating an acetylation and HDAC6-sensitive effect of Fe65 on cell migration and invasion. The increase in cell migration and invasion caused by Fe65 siRNA is smaller than what was detected in Fe65 stable knockdown clones (Fig. 1), possibly due to the effect of transfection reagents or the vehicle (DMSO) for HDAC inhibitors.

Bottom Line: The present study documents for the first time a role of Fe65 in suppressing breast cancer cell migration and invasion.Mechanistic studies suggest that the suppression is mediated through its phosphotyrosine binding domain 1 that mediates the recruitment of Tip60 to cortactin to stimulate its acetylation.The studies identify the Tip60 acetyltransferase as a cytoplasmic drug target for the therapeutic intervention of metastatic breast cancers.

View Article: PubMed Central - PubMed

Affiliation: Departments of Pathology and Cell Biology, University of South Florida Morsani College of Medicine, Tampa, FL 33612.

ABSTRACT
Fe65 is a brain-enriched adaptor protein known for its role in the action of the Aβ amyloid precursor protein in neuronal cells and Alzheimer's disease, but little is known about its functions in cancer cells. The present study documents for the first time a role of Fe65 in suppressing breast cancer cell migration and invasion. Mechanistic studies suggest that the suppression is mediated through its phosphotyrosine binding domain 1 that mediates the recruitment of Tip60 to cortactin to stimulate its acetylation. The studies identify the Tip60 acetyltransferase as a cytoplasmic drug target for the therapeutic intervention of metastatic breast cancers.

No MeSH data available.


Related in: MedlinePlus