Universität zu Köln

Bauer, Simone ORCID: 0000-0003-4296-0870, Ratz, Leonie, Heckmann-Noetzel, Doreen, Kaczorowski, Adam, Hohenfellner, Markus, Kristiansen, Glen, Duensing, Stefan, Altevogt, Peter, Klauck, Sabine M. and Sueltmann, Holger (2021). miR-449a Repression Leads to Enhanced NOTCH Signaling in TMPRSS2:ERG Fusion Positive Prostate Cancer Cells. Cancers, 13 (5). BASEL: MDPI. ISSN 2072-6694

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Abstract

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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Bauer, Simone UNSPECIFIED orcid.org/0000-0003-4296-0870 UNSPECIFIED Ratz, Leonie UNSPECIFIED UNSPECIFIED UNSPECIFIED Heckmann-Noetzel, Doreen UNSPECIFIED UNSPECIFIED UNSPECIFIED Kaczorowski, Adam UNSPECIFIED UNSPECIFIED UNSPECIFIED Hohenfellner, Markus UNSPECIFIED UNSPECIFIED UNSPECIFIED Kristiansen, Glen UNSPECIFIED UNSPECIFIED UNSPECIFIED Duensing, Stefan UNSPECIFIED UNSPECIFIED UNSPECIFIED Altevogt, Peter UNSPECIFIED UNSPECIFIED UNSPECIFIED Klauck, Sabine M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Sueltmann, Holger UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-593407
DOI:	10.3390/cancers13050964
Journal or Publication Title:	Cancers
Volume:	13
Number:	5
Date:	2021
Publisher:	MDPI
Place of Publication:	BASEL
ISSN:	2072-6694
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HISTONE DEACETYLASE; GENE-EXPRESSION; GROWTH ARREST; PROMOTES; ANGIOGENESIS; COMPLEX; HES1; PHOSPHORYLATION; PROLIFERATION; MICRORNA-449 Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/59340