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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.


Related in: MedlinePlus

MTA1 levels negatively correlate with DNMT3a status in human cancer.(A) Levels of MTA1 and DNMT3a mRNAs in four breast and two colon cancer datasets as analyzed using R2: Genomics Analysis and Visualization Platform, and values are presented on a log2 scale. (B) levels of MTA1 and DNMT3a in cancer cells when compared to the normal cells in Oncomine Cancer Profiling Database. Box’s detail: 1, 10, gastric3940; 2, anaplastic oligodendroglioma41; 3, renal cell carcinoma42, 4–5, Ovarian cell carcinoma43; 6–7, Skin4445 and 8–9, colon cancers46 TCGA Colorectal, 2011]. The p-value is provided for the medium-rank analysis. (C) cBioPortal showing the genetic alterations in the DNMT3a and MTA1 in 971 patients obtained from TCGA-Breast cancer dataset; in 877 patients from Cancer cell line encyclopedia; each bar indicates the individual cases; % on the left indicates the percentage of cases altered in MTA1 and DNMT3a. (D) Panel 1: DNMT3a and MTA1 mRNAs in blood, breast, CNS, colon, kidney, lung, ovary, prostate and skin cancer cell lines in NCI-60; Panel 2, DNMT3a and MTA1 mRNAs in 59 breast cancer cell lines; and Panel 3, DNMT3a and MTA1 mRNAs in 61 colon cancer cells analyzed through CAncerREsource2 database. (E) Kaplan-Meier plot of disease specific survival of 117 breast cancer patients stratified by high (red) and low (blue) in the dataset E-TABM-158. (F) Kaplan-Meier plot of disease specific survival of 177 colon cancer patients stratified by high (red) and low (blue) analyzed through PrognoScan database. Dotted lines, 95% confidence intervals for each group.
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f1: MTA1 levels negatively correlate with DNMT3a status in human cancer.(A) Levels of MTA1 and DNMT3a mRNAs in four breast and two colon cancer datasets as analyzed using R2: Genomics Analysis and Visualization Platform, and values are presented on a log2 scale. (B) levels of MTA1 and DNMT3a in cancer cells when compared to the normal cells in Oncomine Cancer Profiling Database. Box’s detail: 1, 10, gastric3940; 2, anaplastic oligodendroglioma41; 3, renal cell carcinoma42, 4–5, Ovarian cell carcinoma43; 6–7, Skin4445 and 8–9, colon cancers46 TCGA Colorectal, 2011]. The p-value is provided for the medium-rank analysis. (C) cBioPortal showing the genetic alterations in the DNMT3a and MTA1 in 971 patients obtained from TCGA-Breast cancer dataset; in 877 patients from Cancer cell line encyclopedia; each bar indicates the individual cases; % on the left indicates the percentage of cases altered in MTA1 and DNMT3a. (D) Panel 1: DNMT3a and MTA1 mRNAs in blood, breast, CNS, colon, kidney, lung, ovary, prostate and skin cancer cell lines in NCI-60; Panel 2, DNMT3a and MTA1 mRNAs in 59 breast cancer cell lines; and Panel 3, DNMT3a and MTA1 mRNAs in 61 colon cancer cells analyzed through CAncerREsource2 database. (E) Kaplan-Meier plot of disease specific survival of 117 breast cancer patients stratified by high (red) and low (blue) in the dataset E-TABM-158. (F) Kaplan-Meier plot of disease specific survival of 177 colon cancer patients stratified by high (red) and low (blue) analyzed through PrognoScan database. Dotted lines, 95% confidence intervals for each group.

Mentions: To explore the nature of relationship between the status of MTA1 and DNMT3a in human cancer, we first interrogated the available breast and colon microarray public datasets for the levels of DNMT3a and MTA1. We noticed an inverse relationship between the levels of MTA1 and DNMT3a mRNAs in all data sets analyzed (Fig. 1A). As an example, MTA1 upregulation in breast tumors was accompanied by more than 3-fold downregulation of DNMT3a mRNA (Fig. S1, ref. 17). The noted inverse relationship between the levels of MTA1 and DNMT3a mRNAs was not limited to human breast or colon cancer but true for cancer, at-large, in general, when compared with the corresponding normal tissues using Oncomine dataset (Fig. 1B). For example, MTA1 and DNMT3a mRNA levels are significantly upregulated (p = 0.004) and downregulated (p = 3.00E-4) respectively, in gastric, renal, ovarian, skin and colon cancers when compared to the normal tissues (Fig. S2). Like Oncomine datasets, we also found an inverse relationship between the status of MTA1 and DNMT3a mRNAs in 971 cases of breast cancers from the TCGA dataset analyzed using cBioPortal tools (Fig. 1C). Next, we examined the status of MTA1 and DNMT3a in 877 cases from the Cancer Cell Line Encyclopedia using cBioPortal database. Once again, we found a remarkable reverse relationship between MTA1 upregulation and DNMT3a downregulation in most cancer types with a low degree of exception to this relationship (Fig. 1D). We also noticed an inverse relationship between the levels of MTA1 and DNMT3a in NCI-60 Panel cell lines as well as in 59 breast and 61 colon cancer cell lines (Fig. 1D).


Metastasis-associated protein 1 is an upstream regulator of DNMT3a and stimulator of insulin-growth factor binding protein-3 in breast cancer
MTA1 levels negatively correlate with DNMT3a status in human cancer.(A) Levels of MTA1 and DNMT3a mRNAs in four breast and two colon cancer datasets as analyzed using R2: Genomics Analysis and Visualization Platform, and values are presented on a log2 scale. (B) levels of MTA1 and DNMT3a in cancer cells when compared to the normal cells in Oncomine Cancer Profiling Database. Box’s detail: 1, 10, gastric3940; 2, anaplastic oligodendroglioma41; 3, renal cell carcinoma42, 4–5, Ovarian cell carcinoma43; 6–7, Skin4445 and 8–9, colon cancers46 TCGA Colorectal, 2011]. The p-value is provided for the medium-rank analysis. (C) cBioPortal showing the genetic alterations in the DNMT3a and MTA1 in 971 patients obtained from TCGA-Breast cancer dataset; in 877 patients from Cancer cell line encyclopedia; each bar indicates the individual cases; % on the left indicates the percentage of cases altered in MTA1 and DNMT3a. (D) Panel 1: DNMT3a and MTA1 mRNAs in blood, breast, CNS, colon, kidney, lung, ovary, prostate and skin cancer cell lines in NCI-60; Panel 2, DNMT3a and MTA1 mRNAs in 59 breast cancer cell lines; and Panel 3, DNMT3a and MTA1 mRNAs in 61 colon cancer cells analyzed through CAncerREsource2 database. (E) Kaplan-Meier plot of disease specific survival of 117 breast cancer patients stratified by high (red) and low (blue) in the dataset E-TABM-158. (F) Kaplan-Meier plot of disease specific survival of 177 colon cancer patients stratified by high (red) and low (blue) analyzed through PrognoScan database. Dotted lines, 95% confidence intervals for each group.
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f1: MTA1 levels negatively correlate with DNMT3a status in human cancer.(A) Levels of MTA1 and DNMT3a mRNAs in four breast and two colon cancer datasets as analyzed using R2: Genomics Analysis and Visualization Platform, and values are presented on a log2 scale. (B) levels of MTA1 and DNMT3a in cancer cells when compared to the normal cells in Oncomine Cancer Profiling Database. Box’s detail: 1, 10, gastric3940; 2, anaplastic oligodendroglioma41; 3, renal cell carcinoma42, 4–5, Ovarian cell carcinoma43; 6–7, Skin4445 and 8–9, colon cancers46 TCGA Colorectal, 2011]. The p-value is provided for the medium-rank analysis. (C) cBioPortal showing the genetic alterations in the DNMT3a and MTA1 in 971 patients obtained from TCGA-Breast cancer dataset; in 877 patients from Cancer cell line encyclopedia; each bar indicates the individual cases; % on the left indicates the percentage of cases altered in MTA1 and DNMT3a. (D) Panel 1: DNMT3a and MTA1 mRNAs in blood, breast, CNS, colon, kidney, lung, ovary, prostate and skin cancer cell lines in NCI-60; Panel 2, DNMT3a and MTA1 mRNAs in 59 breast cancer cell lines; and Panel 3, DNMT3a and MTA1 mRNAs in 61 colon cancer cells analyzed through CAncerREsource2 database. (E) Kaplan-Meier plot of disease specific survival of 117 breast cancer patients stratified by high (red) and low (blue) in the dataset E-TABM-158. (F) Kaplan-Meier plot of disease specific survival of 177 colon cancer patients stratified by high (red) and low (blue) analyzed through PrognoScan database. Dotted lines, 95% confidence intervals for each group.
Mentions: To explore the nature of relationship between the status of MTA1 and DNMT3a in human cancer, we first interrogated the available breast and colon microarray public datasets for the levels of DNMT3a and MTA1. We noticed an inverse relationship between the levels of MTA1 and DNMT3a mRNAs in all data sets analyzed (Fig. 1A). As an example, MTA1 upregulation in breast tumors was accompanied by more than 3-fold downregulation of DNMT3a mRNA (Fig. S1, ref. 17). The noted inverse relationship between the levels of MTA1 and DNMT3a mRNAs was not limited to human breast or colon cancer but true for cancer, at-large, in general, when compared with the corresponding normal tissues using Oncomine dataset (Fig. 1B). For example, MTA1 and DNMT3a mRNA levels are significantly upregulated (p = 0.004) and downregulated (p = 3.00E-4) respectively, in gastric, renal, ovarian, skin and colon cancers when compared to the normal tissues (Fig. S2). Like Oncomine datasets, we also found an inverse relationship between the status of MTA1 and DNMT3a mRNAs in 971 cases of breast cancers from the TCGA dataset analyzed using cBioPortal tools (Fig. 1C). Next, we examined the status of MTA1 and DNMT3a in 877 cases from the Cancer Cell Line Encyclopedia using cBioPortal database. Once again, we found a remarkable reverse relationship between MTA1 upregulation and DNMT3a downregulation in most cancer types with a low degree of exception to this relationship (Fig. 1D). We also noticed an inverse relationship between the levels of MTA1 and DNMT3a in NCI-60 Panel cell lines as well as in 59 breast and 61 colon cancer cell lines (Fig. 1D).

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.


Related in: MedlinePlus