Send to

Choose Destination
Antioxid Redox Signal. 2013 May 20;18(15):1946-55. doi: 10.1089/ars.2012.4850. Epub 2012 Oct 18.

Regulation of SOD2 in cancer by histone modifications and CpG methylation: closing the loop between redox biology and epigenetics.

Author information

Free Radical and Radiation Biology Program, Department of Radiation Oncology, and Holden Comprehensive Cancer Center, The University of Iowa, Iowa City, Iowa 52242-1181, USA.



Manganese superoxide dismutase (SOD2), encoded by the nuclear gene SOD2, is a critical mitochondrial antioxidant enzyme whose activity has broad implications in health and disease. Thirty years ago, Oberley and Buettner elegantly folded SOD2 into cancer biology with the free radical theory of cancer, which was built on the observation that many human cancers had reduced SOD2 activity. In the original formulation, the loss of SOD2 in tumor cells produced a state of perpetual oxidative stress, which, in turn, drove genetic instability, leading to cancer development.


In the past two decades, research has established that SOD2 transcriptional activity is controlled, at least in part, via epigenetic mechanisms at different stages in the development of human cancer. These mechanisms, which include histone methylation, histone acetylation, and DNA methylation, are increasingly recognized as being aberrantly regulated in human cancer. Indeed, the epigenetic progenitor model proposed by Henikoff posits that epigenetic events are central governing agents of carcinogenesis. Important recent advances in epigenetics research have indicated that the loss of SOD activity itself may contribute to changes in epigenetic regulation, establishing a vicious cycle that drives further epigenetic instability.


With these observations in mind, we propose an epigenetic revision to the free radical theory of cancer: that loss of SOD activity promotes epigenetic aberrancies, driving the epigenetic instability in tumor cells which produces broad phenotypic effects.


The development of next-generation sequencing technologies and novel approaches in systems biology and bioinformatics promise to make testing this exciting model a reality in the near future.

[Indexed for MEDLINE]
Free PMC Article

Supplemental Content

Full text links

Icon for Atypon Icon for PubMed Central
Loading ...
Support Center