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.
Highlights
A critical regulatory DNA modification is through methylation which acts as a switch for gene expression via interacting with the chromatin remodeling complexes[3]
We found that the levels of MTA1 and DNMT3a are inversely correlate in human cancer at-large, and that low DNMT3a in combination of high MTA1 expression predicts a poor clinical outcome in breast cancer patients
We found that increased levels of MTA1 correlate well with an elevated level of IGFBP3 as well as low DNMT3a and this may result in poor prognosis of breast cancer patients
Summary
A critical regulatory DNA modification is through methylation which acts as a switch for gene expression via interacting with the chromatin remodeling complexes[3]. It is noteworthy to mention that the genetic depletion of Dnmt3a does not lead to a global change the status of net DNA methylation[11], but limits alterations of methylation and expression patterns of specific target genes[12]. These observations suggest that DNMT3a remains a least-understood family member. Low levels of DNMT3a correlates well with a high IGFBP3 expression and associate with a poor distant metastasis-free survival of breast cancer patients. Findings presented here identified an upstream regulatory role of MTA1 coregulator in controlling the expression of DNMT3a and IGFBP3 in cancer cells and possibly modifying the biology of breast cancer progression
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