Epigenetic Regulation of Manganese Superoxide Dismutase Expression in Human Breast Cancer Cells (original) (raw)
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Molecular Cancer Research, 2008
A primary antioxidant enzyme in mitochondria, Manganese superoxide dismutase (MnSOD) plays a critical role in the survival of aerobic life. It is well-documented that compared to normal cell counterparts, MnSOD level is decreased in neoplastic transformed cells but is increased in aggressive cancers. However, the underlying mechanism for the observed dysregulation of MnSOD in cancer is unknown. We have previously identified a unique set of mutations located in the promoter region of the SOD2 gene in several types of cancer cells. We found that a C to T transition at −102 and an insertion of A at −93 downregulate MnSOD transcription by interrupting the formation of a singlestranded loop that is essential for a high level of promoter activity. Here, we demonstrate that the additional downstream mutation, C to G transversion at −38, creates a binding site for the transcription factors specificity protein 1 (Sp1) and activating protein 2 (AP-2). The promoter function is regulated by the relative levels of Sp1 and AP-2. In cytokine-induced expression of the SOD2 gene, Sp1 cooperates with a transcriptional complex containing nuclear factor κB (NF-κB) and nucleophosmin (NPM). The presence of AP-2 attenuates this induction. Our results suggest that the high level of MnSOD observed in aggressive cancer cells may be due, in part, to the absence of AP-2 transcriptional repression.
Breast cancer is one of the most common malignancies of all cancers in women worldwide. Many difficulties reside in the prediction of tumor metastatic progression because of the lack of sufficiently reliable predictive biological markers, and this is a permanent preoccupation for clinicians. Manganese superoxide dismutase (MnSOD) may represent a rational candidate as a predictive biomarker of breast tumor metastatic progression, because its gene expression is profoundly altered between early and advanced breast cancer, in contrast to expression in the normal mammary gland. In this review, we report the characterization of some gene polymorphisms and molecular mechanisms of SOD2 gene regulation, which allows a better understanding of how MnSOD is decreased in early breast cancer and increased in advanced breast cancer. Several studies display the biological significance of MnSOD level in proliferation as well as in invasive and angiogenic abilities of breast tumor cells by controlling superoxide anion radical (O 2
MnSOD/SOD2 in Cancer: The Story of a Double Agent
2018
Manganese-dependent superoxide dismutase (MnSOD/SOD2) is one of the major antioxidant enzymes which scavenges the superoxide produced in the mitochondria, the main source of free radicals in non-pathological conditions. This first barrier is important to prevent early stages of cancer development. However, once the tumor is established, upregulation of MnSOD without a concomitant increase of scavengers of hydrogen peroxide (H2O2) plays a much complex role. It contributes to proliferation, angiogenesis and invasion, affecting glycolytic metabolism and preventing the mitochondria from inducing apoptosis favoring therapy resistance. The increase of H2O2 mediated by MnSODis able to induce phenotypical changes in several tumor types, such as epithelia-mesenchymal transition increasing the motility of tumor cells, neuroendocrine differentiation and senescent secretory phenotypes which feed tumor progression by producing cytokines and growth factors.
Journal of Biomedicine and Biotechnology, 2004
Manganese superoxide dismutase (Mn-SOD), localized at the mitochondrial matrix, has the ability to protect cells against oxidative damage. It has been reported that low levels of Mn-SOD gene expression cause the development of certain kind of tumors. On the other hand, overexpression of Mn-SOD gene may play an important role in the development of cancer. In our study, we find that Mn-SOD activity was higher in nonaggressive (MCF-7) and aggressive (BT-549 and 11-9-14) breast cancer cell lines compared to that of nontumorigenic (MCF-12A and MCF-12F) mammary epithelial cell lines. We also observed an increased expression of Mn-SOD gene in cancerous cell lines. The elevated level of SOD activity in nonaggressive and aggressive breast epithelial cell lines was associated with some changes in nucleotide sequence.
Two polymorphic variants of manganese superoxide dismutase (MnSOD), with either Ile or Thr at amino acid 58, (Ile 58 MnSOD or Thr 58 MnSOD), have been found in the human population. The MnSOD activity of these two variants and their effects on the malignant phenotype of human breast cancer MCF-7 cells were compared. It was demonstrated that MnSOD-overexpressing clones obtained from transfection of the two MnSOD cDNAs into MCF-7 cells had increased MnSOD immunoreactive protein and increased MnSOD activity. Cells overexpressing Ile 58 MnSOD had 3-fold higher MnSOD activity than cells overexpressing Thr 58 MnSOD in vivo at an equal MnSOD protein level. Tumor-suppressive effects of MnSOD-overexpressing cells were indicated by: (a) decreased plating efficiency; (b) elongated cell population doubling time; (c) lower clonogenic fraction in soft agar; and (d) complete inhibition or delayed onset of tumor formation in nude mice.
Human manganese superoxide dismutase suppresses HER2/neu-mediated breast cancer malignancy
Febs Letters, 2007
The up-regulation of HER2/neu is associated with human malignancies and is a useful target for developing anticancer drugs. Overexpression of human manganese superoxide dismutase (MnSOD) has been demonstrated to effectively suppress various carcinoma cells, including breast carcinomas, in vitro and in vivo. This study demonstrates that MnSOD effectively suppresses HER2/neu oncogene expression at the transcriptional level. Additionally, stable transfection was
2004
The most important cellular protective mechanisms against oxidative stress are antioxidant enzymes. Their action is based on decomposal of reactive oxygen species (ROS) and their transformation to H 2 O 2. Within the mitochondria manganese superoxide dismutase (MnSOD) affords the major defense against ROS. In this study we investigated tissue sections from 101 breast carcinomas for the immunohistochemical expression of MnSOD protein and these results were assessed in relation to various clinicopathological parameters, in order to clarify the prognostic value of this enzyme. The possible relationship to hormone receptor content, anti-apoptotic protein bcl-2, p53 and cell proliferation was also estimated. High expression levels were observed, as 79/101 (78,2%) cases expressed strong immunoreactivity. In this study MnSOD increased in a direct relationship with tumor grade and is therefore inversely correlated with differentiation (p=0.0004). Furthermore, there was a strong positive correlation between MnSOD expression and p53 protein immunoreactivity (p=0.0029). The prognostic impact of MnSOD expression in determining the risk of recurrence and overall survival with both univariate (long-rang test) and multivariate (Cox regression) methods of analysis was statistically not significant. These results indicate that neoplastic cells in breast carcinomas retain their capability to produce MnSOD and thus protected from the possible cellular damage provoked by reactive oxygen species. In addition, MnSOD content varies according to the degree of differentiation of breast carcinoma.
Oncogene, 2013
Expression of the antioxidant enzyme EcSOD in normal human mammary epithelial cells was not recognized until recently. Although expression of EcSOD was not detectable in non-malignant human mammary epithelial cells (HMEC) cultured in conventional two-dimensional (2D) culture conditions, EcSOD protein expression was observed in normal human breast tissues, suggesting that the 2D-cultured condition induces a repressive status of EcSOD gene expression in HMEC. With the use of lamininenriched extracellular matrix (lrECM), we were able to detect expression of EcSOD when HMEC formed polarized acinar structures in a 3D-culture condition. Repression of the EcSOD-gene expression was again seen when the HMEC acini were sub-cultured as a monolayer, implying that lrECM-induced acinar morphogenesis is essential in EcSOD-gene activation. We have further shown the involvement of DNA methylation in regulating EcSOD expression in HMEC under these cell culture conditions. EcSOD mRNA expression was strongly induced in the 2D-cultured HMEC after treatment with a DNA methyltransferase inhibitor. In addition, epigenetic analyses showed a decrease in the degree of CpG methylation in the EcSOD promoter in the 3D versus 2D-cultured HMEC. More importantly, 480% of clinical mammary adenocarcinoma samples showed significantly decreased EcSOD mRNA and protein expression levels compared with normal mammary tissues and there is an inverse correlation between the expression levels of EcSOD and the clinical stages of breast cancer. Combined bisulfite restriction analysis analysis of some of the tumors also revealed an association of DNA methylation with the loss of EcSOD expression in vivo. Furthermore, overexpression of EcSOD inhibited breast cancer metastasis in both the experimental lung metastasis model and the syngeneic mouse model. This study suggests that epigenetic silencing of EcSOD may contribute to mammary tumorigenesis and that restoring the extracellular superoxide scavenging activity could be an effective strategy for breast cancer treatment.