TY  - JOUR
AU  - Hamdan, Feda H
AU  - Abdelrahman, Amro M
AU  - Kutschat, Ana Patricia
AU  - Wang, Xin
AU  - Ekstrom, Thomas L
AU  - Jalan-Sakrikar, Nidhi
AU  - Wegner Wippel, Catherine
AU  - Taheri, Negar
AU  - Tamon, Liezel
AU  - Kopp, Waltraut
AU  - Aggrey-Fynn, Joana
AU  - Bhagwate, Aditya V
AU  - Alva-Ruiz, Roberto
AU  - Lynch, Isaac
AU  - Yonkus, Jennifer
AU  - Kosinsky, Robyn Laura
AU  - Gaedcke, Jochen
AU  - Hahn, Stephan A
AU  - Siveke, Jens
AU  - Graham, Rondell
AU  - Najafova, Zeynab
AU  - Hessmann, Elisabeth
AU  - Truty, Mark J
AU  - Johnsen, Steven A
TI  - Interactive enhancer hubs (iHUBs) mediate transcriptional reprogramming and adaptive resistance in pancreatic cancer.
JO  - Gut
VL  - 72
IS  - 6
SN  - 0017-5749
CY  - London
PB  - BMJ Publishing Group
M1  - DKFZ-2023-00477
SP  - 1174-1185
PY  - 2023
N1  - 2023 Jun;72(6):1174-1185
AB  - Pancreatic ductal adenocarcinoma (PDAC) displays a remarkable propensity towards therapy resistance. However, molecular epigenetic and transcriptional mechanisms enabling this are poorly understood. In this study, we aimed to identify novel mechanistic approaches to overcome or prevent resistance in PDAC.We used in vitro and in vivo models of resistant PDAC and integrated epigenomic, transcriptomic, nascent RNA and chromatin topology data. We identified a JunD-driven subgroup of enhancers, called interactive hubs (iHUBs), which mediate transcriptional reprogramming and chemoresistance in PDAC.iHUBs display characteristics typical for active enhancers (H3K27ac enrichment) in both therapy sensitive and resistant states but exhibit increased interactions and production of enhancer RNA (eRNA) in the resistant state. Notably, deletion of individual iHUBs was sufficient to decrease transcription of target genes and sensitise resistant cells to chemotherapy. Overlapping motif analysis and transcriptional profiling identified the activator protein 1 (AP1) transcription factor JunD as a master transcription factor of these enhancers. JunD depletion decreased iHUB interaction frequency and transcription of target genes. Moreover, targeting either eRNA production or signaling pathways upstream of iHUB activation using clinically tested small molecule inhibitors decreased eRNA production and interaction frequency, and restored chemotherapy responsiveness in vitro and in vivo. Representative iHUB target genes were found to be more expressed in patients with poor response to chemotherapy compared with responsive patients.Our findings identify an important role for a subgroup of highly connected enhancers (iHUBs) in regulating chemotherapy response and demonstrate targetability in sensitisation to chemotherapy.
KW  - chemotherapy (Other)
KW  - drug resistance (Other)
KW  - gene regulation (Other)
KW  - molecular oncology (Other)
KW  - pancreatic cancer (Other)
LB  - PUB:(DE-HGF)16
C6  - pmid:36889906
DO  - DOI:10.1136/gutjnl-2022-328154
UR  - https://inrepo02.dkfz.de/record/274182
ER  -