Limits...
Metastasis-associated protein 1 is an upstream regulator of DNMT3a and stimulator of insulin-growth factor binding protein-3 in breast cancer

View Article: PubMed Central - PubMed

ABSTRACT

Despite a recognized role of DNA methyltransferase 3a (DNMT3a) in human cancer, the nature of its upstream regulator(s) and relationship with the master chromatin remodeling factor MTA1, continues to be poorly understood. Here, we found an inverse relationship between the levels of MTA1 and DNMT3a in human cancer and that high levels of MTA1 in combination of low DNMT3a status correlates well with poor survival of breast cancer patients. We discovered that MTA1 represses DNMT3a expression via HDAC1/YY1 transcription factor complex. Because IGFBP3 is an established target of DNMT3a, we investigated the effect of MTA1 upon IGFBP3 expression, and found a coactivator role of MTA1/c-Jun/Pol II coactivator complex upon the IGFBP3 transcription. In addition, MTA1 overexpression correlates well with low levels of DNMT3a which, in turn also correlates with a high IGFBP3 status in breast cancer patients and predicts a poor clinical outcome for breast cancer patients. These findings suggest that MTA1 could regulate the expression of IGFBP3 in both DNMT3a-dependent and -independent manner. Together findings presented here recognize an inherent role of MTA1 as a modifier of DNMT3a and IGFBP3 expression, and consequently, the role of MTA1-DNMT3a-IGFBP3 axis in breast cancer progression.

No MeSH data available.


MTA1 regulates DNMT3a mRNA.(A,B) qPCR analysis of MTA1 and DNMT3a mRNA in MCF-7 cells and SKBR-3 cells upon overexpressing MTA1 as compared with the control vector. Results are presented as fold change after normalizing with β-actin and 18 S rRNA, respectively. (C) qPCR analysis of MTA1 and DNMT3a mRNA in MCF-7 upon MTA1 silencing as compared with the control vector. (D) qPCR analysis of MTA1 and DNMT3a mRNA in HCT116 by overexpressing MTA1 compared with the vector control. Results are presented as fold change after normalizing with β-actin. (E) qPCR analysis of DNMT3a in MTA1+/+ and MEF MTA1−/− MEFs. Results are presented as fold change after normalizing with β-actin. (*p < 0.01, **p < 0.001, ***p < 0.0001)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC5385551&req=5

f3: MTA1 regulates DNMT3a mRNA.(A,B) qPCR analysis of MTA1 and DNMT3a mRNA in MCF-7 cells and SKBR-3 cells upon overexpressing MTA1 as compared with the control vector. Results are presented as fold change after normalizing with β-actin and 18 S rRNA, respectively. (C) qPCR analysis of MTA1 and DNMT3a mRNA in MCF-7 upon MTA1 silencing as compared with the control vector. (D) qPCR analysis of MTA1 and DNMT3a mRNA in HCT116 by overexpressing MTA1 compared with the vector control. Results are presented as fold change after normalizing with β-actin. (E) qPCR analysis of DNMT3a in MTA1+/+ and MEF MTA1−/− MEFs. Results are presented as fold change after normalizing with β-actin. (*p < 0.01, **p < 0.001, ***p < 0.0001)

Mentions: The noticed modulation of DNMT3a expression by MTA1 was also reflected at the level of mRNA as MTA1 overexpression downregulates the levels of DNMT3a mRNA in MCF-7 (Fig. 3A) and SKBR-3 cells (Fig. 3B) significantly (p < 0.001); conversely, MTA1 knockdown leads to an increased level of DNMT3a mRNA in MCF-7 cells (p < 0.01) (Fig. 3C); marked reduction in DNMT3a mRNA levels were seen when MTA1 is overexpressed in HCT116 cells (Fig. 3D). MTA1-depletion in MTA1-KO MEFs leads to an increased significant level of DNMT3a mRNA (p < 0.01) as compared to wild-type MEF (Fig. 3E). In brief, these findings revealed that MTA1 is an upstream regulator of DNMT3a expression.


Metastasis-associated protein 1 is an upstream regulator of DNMT3a and stimulator of insulin-growth factor binding protein-3 in breast cancer
MTA1 regulates DNMT3a mRNA.(A,B) qPCR analysis of MTA1 and DNMT3a mRNA in MCF-7 cells and SKBR-3 cells upon overexpressing MTA1 as compared with the control vector. Results are presented as fold change after normalizing with β-actin and 18 S rRNA, respectively. (C) qPCR analysis of MTA1 and DNMT3a mRNA in MCF-7 upon MTA1 silencing as compared with the control vector. (D) qPCR analysis of MTA1 and DNMT3a mRNA in HCT116 by overexpressing MTA1 compared with the vector control. Results are presented as fold change after normalizing with β-actin. (E) qPCR analysis of DNMT3a in MTA1+/+ and MEF MTA1−/− MEFs. Results are presented as fold change after normalizing with β-actin. (*p < 0.01, **p < 0.001, ***p < 0.0001)
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC5385551&req=5

f3: MTA1 regulates DNMT3a mRNA.(A,B) qPCR analysis of MTA1 and DNMT3a mRNA in MCF-7 cells and SKBR-3 cells upon overexpressing MTA1 as compared with the control vector. Results are presented as fold change after normalizing with β-actin and 18 S rRNA, respectively. (C) qPCR analysis of MTA1 and DNMT3a mRNA in MCF-7 upon MTA1 silencing as compared with the control vector. (D) qPCR analysis of MTA1 and DNMT3a mRNA in HCT116 by overexpressing MTA1 compared with the vector control. Results are presented as fold change after normalizing with β-actin. (E) qPCR analysis of DNMT3a in MTA1+/+ and MEF MTA1−/− MEFs. Results are presented as fold change after normalizing with β-actin. (*p < 0.01, **p < 0.001, ***p < 0.0001)
Mentions: The noticed modulation of DNMT3a expression by MTA1 was also reflected at the level of mRNA as MTA1 overexpression downregulates the levels of DNMT3a mRNA in MCF-7 (Fig. 3A) and SKBR-3 cells (Fig. 3B) significantly (p < 0.001); conversely, MTA1 knockdown leads to an increased level of DNMT3a mRNA in MCF-7 cells (p < 0.01) (Fig. 3C); marked reduction in DNMT3a mRNA levels were seen when MTA1 is overexpressed in HCT116 cells (Fig. 3D). MTA1-depletion in MTA1-KO MEFs leads to an increased significant level of DNMT3a mRNA (p < 0.01) as compared to wild-type MEF (Fig. 3E). In brief, these findings revealed that MTA1 is an upstream regulator of DNMT3a expression.

View Article: PubMed Central - PubMed

ABSTRACT

Despite a recognized role of DNA methyltransferase 3a (DNMT3a) in human cancer, the nature of its upstream regulator(s) and relationship with the master chromatin remodeling factor MTA1, continues to be poorly understood. Here, we found an inverse relationship between the levels of MTA1 and DNMT3a in human cancer and that high levels of MTA1 in combination of low DNMT3a status correlates well with poor survival of breast cancer patients. We discovered that MTA1 represses DNMT3a expression via HDAC1/YY1 transcription factor complex. Because IGFBP3 is an established target of DNMT3a, we investigated the effect of MTA1 upon IGFBP3 expression, and found a coactivator role of MTA1/c-Jun/Pol II coactivator complex upon the IGFBP3 transcription. In addition, MTA1 overexpression correlates well with low levels of DNMT3a which, in turn also correlates with a high IGFBP3 status in breast cancer patients and predicts a poor clinical outcome for breast cancer patients. These findings suggest that MTA1 could regulate the expression of IGFBP3 in both DNMT3a-dependent and -independent manner. Together findings presented here recognize an inherent role of MTA1 as a modifier of DNMT3a and IGFBP3 expression, and consequently, the role of MTA1-DNMT3a-IGFBP3 axis in breast cancer progression.

No MeSH data available.