Related Experiment Video
Updated: Aug 7, 2025
Author Spotlight: Reprogramming Cancer Cells to iPSCs to Study Disease Progression and Treatment Targets
Published on: February 2, 2024
Interactive enhancer hubs (iHUBs) mediate transcriptional reprogramming and adaptive resistance in pancreatic cancer
Feda H Hamdan1,2, Amro M Abdelrahman3, Ana Patricia Kutschat4
1Division of Gastroenterology and Hepatology, Mayo Clinic, Rochester, Minnesota, USA Steven.Johnsen@bosch-health-campus.com Hamdan.Feda@mayo.edu.
Objective:
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.
Design:
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.
Results:
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.
Conclusion:
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.
Insights
Researchers discovered JunD-driven interactive hubs (iHUBs) that drive pancreatic cancer chemoresistance. Targeting these iHUBs or upstream pathways can re-sensitize resistant pancreatic ductal adenocarcinoma (PDAC) to chemotherapy.
Area of Science:
- Cancer Biology
- Epigenetics
- Molecular Oncology
Background:
- Pancreatic ductal adenocarcinoma (PDAC) is highly resistant to therapy.
- The molecular mechanisms underlying PDAC therapy resistance are not well understood.
- Identifying novel strategies to overcome resistance is crucial for improving patient outcomes.
Purpose of the Study:
- To identify novel molecular and epigenetic mechanisms driving PDAC therapy resistance.
- To explore potential therapeutic targets for overcoming chemoresistance in PDAC.
- To investigate the role of enhancers in mediating transcriptional reprogramming and chemoresistance.
Main Methods:
- Utilized in vitro and in vivo models of resistant PDAC.
- Integrated epigenomic, transcriptomic, nascent RNA, and chromatin topology data.
- Performed motif analysis and transcriptional profiling to identify key transcription factors.
Main Results:
- Identified JunD-driven interactive hubs (iHUBs) that regulate transcriptional reprogramming and chemoresistance in PDAC.
- iHUBs show increased interactions and enhancer RNA (eRNA) production in resistant states.
- Targeting iHUBs or upstream pathways restored chemotherapy responsiveness in vitro and in vivo.
- JunD depletion or inhibition of eRNA production sensitized resistant cells to chemotherapy.
Conclusions:
- A subgroup of highly connected enhancers (iHUBs) plays a critical role in regulating chemotherapy response in PDAC.
- These iHUBs are targetable for sensitizing PDAC to chemotherapy.
- JunD is a master transcription factor regulating these resistance-mediating enhancers.
Related Concept Videos
02:53Adaptive Mechanisms in Cancer Cells
Some of the advantages that cancer cells have on normal cells include - enhanced ability to divide without terminally differentiating, induce new blood vessel formation,...
01:29Somatic to iPS Cell Reprogramming
01:06Induced Pluripotent Stem Cells
Somatic...
01:19Interactions Between Signaling Pathways
Convergence and divergence, and cross-talk between signaling pathways
Two distinct signaling pathways can converge on a single functional unit, which may either be a single protein or a complex of proteins. The response is either functionally distinct or synergistic between the two pathways but different from the response...
02:40Cancer Stem Cells and Tumor Maintenance
Cancer stem cells are thought to originate from tissue-specific normal stem cells or progenitor cells. The normal stem cells usually reside in...
01:32Chromatin Modification in iPS Cells
Compact chromatin makes reprogramming difficult. Enzymes, such as histone demethylases and acetyltransferases, are often added during reprogramming to loosen the chromatin, making the DNA more accessible to transcription factors. Molecules that inhibit histone...