Prostate Cancer Progression and the Epigenome

Abstract

Efforts to translate laboratory-based discovery into clinical applications and to transform medical-oncology problems into research questions have been made particularly challenging by the natural history of prostate cancer. To begin, widespread screening and early diagnostic programs through noninvasive testing (e.g., analysis of serum prostate-specific antigen [PSA] and urinary prostate cancer antigen 3) have restricted the amount of available tumor tissue for molecular studies. Moreover, despite the high incidence of prostate cancer in men, the disease is virtually absent in other mammals (including captive non-human primates), thereby eliminating natural animal models. Many prostate cancers are organ-confined when diagnosed, and long follow-up (10 to 15 years) is required to detect a survival advantage. Given these practical limitations of tumor procurement and timeline constraints, it is often difficult to obtain matched samples of normal (nonmalignant) prostate gland, organ-confined prostate cancer, and bone metastasis from pros-tate cancer to analyze tumor progression on a molecular level in order to advance mechanism-based treatment strategies. Prostate cancer is driven by interrelated genetic 1,2 and epigenetic 3 alterations. Known genetic contributors to sporadic prostate cancer are the presence of germline genetic variants that increase the risk of prostate cancer and of somatic mutations, rearrangements, or irregular expression of noncoding RNAs that promote tumori-genesis and metastasis. Central to the patho-physiological mechanisms of prostate cancer is the androgen receptor, a master transcription factor (i.e., a protein that binds to DNA or chro-matin and regulates the expression of a number of genes) (Fig. 1). 1-3 How the epigenome contributes to tumor progression is less well understood. The epigenome includes DNA methylation and histone modifications (e.g., acetylation or methyl-ation) that repress or activate gene expression; in some cases, such activity perpetuates an open chromatin state, which can preserve the potential for repression or activation of gene expression. (Changes in the chromatin structure resulting from certain mutations have been linked to the development of disease.) In a binational Dutch-American collaboration, Pomerantz and colleagues 4 integrated public epi-genomic information from adult and fetal databases with a massive epigenomic data set regarding normal prostate epithelium, localized prostate cancer, and patient-derived xenograft models of metastasis. The data set regarding models of metastasis included genomewide binding patterns of the androgen receptor and two additional transcription factors-HOXB13 and FOXA1-that are key to both prostate development and prostate cancer. It also included an epigenetic hallmark of active gene regulatory elements: acetylation of histone H3 at lysine 27 (H3K27ac). During these investigations, the researchers made three discoveries. The first helps to explain how the reprogramming of the epigenome by the androgen receptor occurs during prostate cancer progression. Metastasis-specific androgen-receptor-binding sites coincide with chromatin that is already open in normal prostate epithe-lium and localized prostate cancer. Furthermore, these preexisting sites of open chromatin are premarked by HOXB13 and FOXA1 (i.e., the transcription factors are already present in the normal prostate gland) (Fig. 2). Presumably, these proteins directly or indirectly provide access to genetic regulatory regions by the androgen receptor in metastatic tumor cells. The presence of these guideposts in normal prostate tissue presents a potential entry point for investigational intervention. The New England Journal of Medicine Downloaded from nejm.org at UNIVERSITA DEGLI STUDI DI PADOVA on January 3, 2024. For personal use only. No other uses without permission.