The E2F1/DNMT1 Axis Represses AR in Both Normal and Malignant Prostate Epithelium.

[摘要] The molecular events associated with the recurrence of castration resistant prostate cancer (CRPC) are of critical importance in prostate cancer research, as CRPC is associated with high morbidity and lethality.CRPC is associated with deregulated prostatic epithelium exhibiting decreased AR expression in over 30% of the cases and seems to mimic the proliferative AR-negative undifferentiated transit amplifying (T/A) cells of the developing prostate.In an effort to further characterize this proliferative and undifferentiated cell population, we evaluated possible mechanisms involved in AR gene repression.We have shown that E2F1, a known transcriptional activator, represses AR expression. To explore this mechanism further, we overexpressed E2F1 in prostate epithelial cells and found that AR levels decreased while a dominant negative E2F1 construct reversed the inhibitory effects on AR transcription. E2F1 activates the transcription of DNMT1, a protein that typically silences genes through DNA methylation, however, we found that DNMT1 repressed the AR gene in a DNA methylation independent fashion.We further explored the E2F1/DNMT1/AR regulatory axis in a CRPC mouse model.Heightened E2F1 expression was previously shown to be inversely correlated with AR expression during human prostate cancer progression to CRPC.We demonstrated that DNMT1 nuclear staining significantly increased from benign tissue to treatment resistant, metastatic prostate cancer in humans.Considering that abnormal levels of DNMT1 may methylate and repress AR, we evaluated tissue from CRPC mice injected with a DNA methylation inhibitor, 5-aza. A rise in AR positive tissue corresponded with a decrease in the amount of DNMT1 nuclear staining following treatment.The immunohistochemical data suggests that hypermethylation mediated repression of the AR gene by DNMT1 during the development of CRPC may represent an important etiological aspect of this disease.In summary, we have identified a mechanism of AR repression mediated by the E2F1/DNMT1 axis that results in methylation independent AR repression in proliferative, undifferentiated prostate epithelium.However, AR repression also identified in neoplastic cells appears to be dependent on DNA methylation during the emergence of CRPC. Our studies reveal novel epigenetic regulatory mechanisms involved in AR repression that may further elucidate the understanding of transcriptional regulation, particularly in CRPC.

[发布机构] University of Michigan

[效力级别] Molecular

[关键词] Repression of AR by E2F1/DNMT1 Axis;Molecular;Cellular and Developmental Biology;Health Sciences;Cellular & Molecular Biology