Modulation of Genomic Imprinting by Oxidative Stress

University Of Wisconsin Madison, Madison WI

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Abstract

Features of altered growth regulation in the prostate that will be addressed in the present proposal include the generalized or field change in cancer susceptibility and its age-dependence. Alterations in genomic imprinting are important in the development of preneoplastic lesions and cancer. IGF-II is an auto-paracrine growth stimulator that is an important positive modulator of growth and cancer development. We have demonstrated that loss of IGF-II imprinting (LOI)is an age-related specific epigenetic alteration that occurs in the peripheral prostate of the human. The imprinting of IGF-II in adult tissues is typically maintained and LOI is a common attribute of prostate cancers. One candidate underlying these changes in imprinting is oxidative stress. We provide preliminary evidence that augmented oxidative stress leads to a loss of imprinting in prostate epithelial cells in vitro. It is our hypothesis to be tested that a loss of genomic imprinting in IGF-II in prostate epithelial cells in vivo is accelerated by oxidative stress, and furthermore that this imprinting change is linked to alterations in DNA methylation. Since DNA methylation is a major determinant of IGF-II imprinting we would anticipate that regional changes in methylation would be associated with altered imprinting status. We will generate a unique mouse model of oxidative stress in which CuZn superoxide dismutase(SOD) is inactivated and informative polymorphisms for the IGF-II locus occur. In Specific Aim 1, we will determine if oxidative stress induces a LOI of IGF-II in the mouse prostate. In Specific Aim 2, we will mechanistically link changes in DNA methylation with changes in oxidative stress and imprinting. Furthermore, antioxidants will be utilized to reverse these epigenetic alterations. This proposal is significant and novel in that it has the ability to provide a critical epigenetic link between a ubiquitous process, oxidative stress, and regulation of a detrimental growth factor in vivo. Given data that IGF-II LOI occurs in normal tissues associated with other age-related cancers, including breast and colon, these studies will have larger implications with regard to the development of cancer susceptibility. Even in the unlikely event the IGF-II plays only a minor role in prostate carcinogenesis, this proposal represents a novel and important methodological approach to evaluating epigenetic field changes that may explain the age-, organ- and diet-related specificity of prostate cancer.