Editorial Targeting Epigenetics to Prevent Obesity Promoted Cancers Nathan A. Berger 1,2,3 and Peter C. Scacheri 4 Abstract Epigenetic changes in DNA and associated chromatin proteins are increasingly being considered as important mediators of the linkage between obesity and cancer. Although multiple agents, targeted at epigenetic changes, are being tested for therapy of established cancers, this issue of Cancer Prevention Research carries two articles demonstrating that the bromodomain inhibitor I-BET- 762 can attenuate adipose tissue–promoted cancers. Although I-BET-762 significantly delayed, rather than completely prevented, the onset of adiposity-promoted transformation and malignancy, these experiments pro- vide important proof of principle for the strategies of targeting epigenetic changes to disrupt the obesity–cancer linkage. Because bromodomain proteins represent only one of multiple epigenetic mediators, it is probable that targeting other epigenetic processes, alone or in combi- nation, may serve to even more effectively disrupt the obesity promotion of cancer. Given the magnitude of the current obesity pandemic and its impact on cancer, preventive measures to disrupt this linkage are critically important. Cancer Prev Res; 11(3); 125–8. Ó2018 AACR. See related article by Chakraborty et al., p. 129 Obesity is associated with increased and worse prog- nosis for multiple malignancies (1, 2). Even early-age obesity may elevate the risk of subsequent adult malig- nancy (3, 4). Although multiple metabolic mechanisms may mediate the obesity–cancer linkage (5), the sus- tained, latent effects of obesity suggest the possibility that it may lead to more durable genetic and/or epi- genetic alterations that promote cancer development over extended periods of time. These epigenetic effects, which are mediated by covalent modification of chro- matin DNA and proteins, that alter genetic readout without changing nucleotide sequence, have now become targets for both cancer chemotherapy and can- cer chemoprevention (6). Because it is theoretically possible to interfere with epigenetic regulation without cytotoxic consequences, this approach to chemopreven- tion is especially of interest for disrupting the obesity– cancer linkage. This issue of Cancer Prevention Research contains articles from the Bernard and the Liby labo- ratories at Michigan State University (East Lansing, MI), reporting that an epigenetic targeting agent, I-BET-762, can attenuate and may eventually contribute to preven- tion of obesity-mediated carcinogenesis in a mouse model (7, 8). This strategy of targeting epigenetic changes to prevent obesity-promoted cancer represents the convergence, over 70 years, of multiple research disciplines including: (i) Epidemiologic studies showing that nutritional stress can impact delayed and even heritable traits. (ii) Chromatin research demonstrating multiple molecular alterations and mediators, which can change gene expression without changing base sequence, sometimes in a heritable epigenetic process. (iii) Intensive structure–activity pharmacologic research to develop agents targeting epigenetic processes; and (iv) Clinical and molecular studies identifying cancer-promoting epigenetic effects of obesity and interventions to disrupt these linkages. Early Nutritional Impact on Adult Disease Multiple epidemiologic and laboratory model studies now indicate that epigenetic effects of prenatal and early childhood nutrition can impact age-related disease occur- ring long after the initial exposure. Studies of preconcep- tion and perinatal nutrition experiences, including the € Overkalix Famine 1836, the Dutch Hunger Winter 1 Department of Medicine, Center for Science, Health & Society, Case Compre- hensive Cancer Center, Case Western Reserve University School of Medicine, Cleveland, Ohio. 2 Department of Biochemistry, Case Western Reserve Univer- sity School of Medicine, Cleveland, Ohio. 3 Department of Genetics & Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio. 4 Department of Genetics & Genome Sciences, Case Western Reserve University School of Medicine, Cleveland, Ohio. Corresponding Author: Nathan A. Berger, Case Western Reserve University, 10900 Euclid Avenue, Cleveland, OH 44106-4971. Phone: 216-368-4084; Fax: 216-368-3244; E-mail: nab@case.edu doi: 10.1158/1940-6207.CAPR-18-0043 Ó2018 American Association for Cancer Research. Cancer Prevention Research www.aacrjournals.org 125 Research. on June 17, 2020. © 2018 American Association for Cancer cancerpreventionresearch.aacrjournals.org Downloaded from Published OnlineFirst February 23, 2018; DOI: 10.1158/1940-6207.CAPR-18-0043