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Aging and Cancer-Related Loss of Insulin-like Growth Factor 2 Imprinting in the Mouse and Human Prostate

¹ Department of Urology, ² Environmental and Molecular Toxicology Program, University of Wisconsin School of Medicine and Public Health, Departments of ³ Genetics, ⁴ Comparative Biosciences, School of Veterinary Medicine, University of Wisconsin, ⁵ Department of Medicine and the Veterans Administration Geriatric Research Education and Clinical Center, and ⁶ Paul P. Carbone Comprehensive Cancer Center, Madison, Wisconsin

Requests for reprints: David F. Jarrard, 600 Highland Avenue, K6/530, Madison, WI 53792. Phone: 608-263-9534; Fax: 608-265-8133; E-mail: jarrard{at}surgery.wisc.edu.

Key Words: imprinting • CTCF • prostate cancer • aging • IGF2

Loss of imprinting (LOI) is an epigenetic alteration involving loss of parental origin-specific expression at normally imprinted genes. A LOI for Igf2, a paracrine growth factor, is important in cancer progression. Epigenetic modifications may be altered by environmental factors. However, is not known whether changes in imprinting occur with aging in prostate and other tissues susceptible to cancer development. We found a LOI for Igf2 occurs specifically in the mouse prostate associated with increased Igf2 expression during aging. In older animals, expression of the chromatin insulator protein CTCF and its binding to the Igf2-H19 imprint control region was reduced. Forced down-regulation of CTCF leads to Igf2 LOI. We further show that Igf2 LOI occurs with aging in histologically normal human prostate tissues and that this epigenetic alteration was more extensive in men with associated cancer. This finding may contribute to a postulated field of cancer susceptibility that occurs with aging. Moreover, Igf2 LOI may serve as a marker for the presence of prostate cancer. [Cancer Res 2008;68(16):6797–802]

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