Insights into the Dichotomous Regulation of SOD2 in Cancer

• Published in: Antioxidants 2017-11, Vol.6 (4), p.86
• Main Authors: Kim, Yeon Soo, Gupta Vallur, Piyushi, Phaëton, Rébécca, Mythreye, Karthikeyan, Hempel, Nadine
• Format: Article
• Language: English
• Subjects: Antioxidants; Cancer; Developmental stages; Epigenetics; Gene regulation; Hydrogen peroxide; Macromolecules; Manganese; Metastases; Microenvironments; Mitochondria; MnSOD; Post-translation; Review; SOD2; SOD2 regulation; Superoxide dismutase; Transcription activation; Transcription factors; Tumor cells; Tumor suppressor genes; Tumorigenesis
• ISSN: 2076-3921; 2076-3921
• DOI: 10.3390/antiox6040086

While loss of antioxidant expression and the resultant oxidant-dependent damage to cellular macromolecules is key to tumorigenesis, it has become evident that effective oxidant scavenging is conversely necessary for successful metastatic spread. This dichotomous role of antioxidant enzymes in cancer highlights their context-dependent regulation during different stages of tumor development. A prominent example of an antioxidant enzyme with such a dichotomous role and regulation is the mitochondria-localized manganese superoxide dismutase SOD2 (MnSOD). SOD2 has both tumor suppressive and promoting functions, which are primarily related to its role as a mitochondrial superoxide scavenger and H₂O₂ regulator. However, unlike true tumor suppressor- or onco-genes, the gene is not frequently lost, or rarely mutated or amplified in cancer. This allows to be either repressed or activated contingent on context-dependent stimuli, leading to its dichotomous function in cancer. Here, we describe some of the mechanisms that underlie SOD2 regulation in tumor cells. While much is known about the transcriptional regulation of the gene, including downregulation by epigenetics and activation by stress response transcription factors, further research is required to understand the post-translational modifications that regulate SOD2 activity in cancer cells. Moreover, future work examining the spatio-temporal nature of SOD2 regulation in the context of changing tumor microenvironments is necessary to allows us to better design oxidant- or antioxidant-based therapeutic strategies that target the adaptable antioxidant repertoire of tumor cells.