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Simple Summary: The reason for the frequent presence of the TMPRSS2:ERG (T2E) gene fusion in prostate cancer (PCa) is not fully understood. We were interested in investigating epigenomic alterations associated with the T2E gene fusion in PCa cells. Making use of publicly available genome-wide data and in vitro analyses using an LNCaP cell line model with inducible T2E expression, we uncovered a molecular network driving NOTCH signaling in T2E-positive PCa. We show that ERG directly activates NOTCH1 and HES1 expression by interacting with their promoter regions. Furthermore, NOTCH is activated by downregulation of miR-449a in ERG overexpressing cells. Experimental NOTCH pathway inhibition as well as HES1 knockdown reduced oncogenic capacities in vitro, suggesting that the NOTCH pathway triggers oncogenic processes in TMPRSS2:ERG-positive PCa. HES1 and ERG expression are correlated in tissue samples from PCa patients. Our data suggest a novel epigenomic network driving NOTCH signaling in T2E+ PCa cells. About 50% of prostate cancer (PCa) tumors are TMPRSS2:ERG (T2E) fusion-positive (T2E+), but the role of T2E in PCa progression is not fully understood. We were interested in investigating epigenomic alterations associated with T2E+ PCa. Using different sequencing cohorts, we found several transcripts of the miR-449 cluster to be repressed in T2E+ PCa. This repression correlated strongly with enhanced expression of NOTCH and several of its target genes in TCGA and ICGC PCa RNA-seq data. We corroborated these findings using a cellular model with inducible T2E expression. Overexpression of miR-449a in vitro led to silencing of genes associated with NOTCH signaling (NOTCH1, HES1) and HDAC1. Interestingly, HDAC1 overexpression led to the repression of HES6, a negative regulator of the transcription factor HES1, the primary effector of NOTCH signaling, and promoted cell proliferation by repressing the cell cycle inhibitor p21. Inhibition of NOTCH as well as knockdown of HES1 reduced the oncogenic properties of PCa cell lines. Using tissue microarray analysis encompassing 533 human PCa cores, ERG-positive areas exhibited significantly increased HES1 expression. Taken together, our data suggest that an epigenomic regulatory network enhances NOTCH signaling and thereby contributes to the oncogenic properties of T2E+ PCa. [ABSTRACT FROM AUTHOR]