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Updated: Sep 30, 2025
Measurements of Physiological Stress Responses in C. Elegans
Published on: May 21, 2020
Oxidative Stress and Cancer Heterogeneity Orchestrate NRF2 Roles Relevant for Therapy Response
Koraljka Gall Trošelj1, Marko Tomljanović1, Morana Jaganjac2
1Laboratory for Epigenomics, Division of Molecular Medicine, Rudjer Boskovic Institute, 10000 Zagreb, Croatia.
Abstract:
Oxidative stress and its end-products, such as 4-hydroxynonenal (HNE), initiate activation of the Nuclear Factor Erythroid 2-Related Factor 2 (NRF2)/Kelch Like ECH Associated Protein 1 (KEAP1) signaling pathway that plays a crucial role in the maintenance of cellular redox homeostasis. However, an involvement of 4-HNE and NRF2 in processes associated with the initiation of cancer, its progression, and response to therapy includes numerous, highly complex events. They occur through interactions between cancer and stromal cells. These events are dependent on many cell-type specific features. They start with the extent of NRF2 binding to its cytoplasmic repressor, KEAP1, and extend to the permissiveness of chromatin for transcription of Antioxidant Response Element (ARE)-containing genes that are NRF2 targets. This review will explore epigenetic molecular mechanisms of NRF2 transcription through the specific molecular anatomy of its promoter. It will explain the role of NRF2 in cancer stem cells, with respect to cancer therapy resistance. Additionally, it also discusses NRF2 involvement at the cross-roads of communication between tumor associated inflammatory and stromal cells, which is also an important factor involved in the response to therapy.
Insights
Oxidative stress activates the NRF2 pathway, crucial for cell balance. This review explores how NRF2 and HNE influence cancer initiation, progression, and therapy response through complex cellular interactions and epigenetic regulation.
Area of Science:
- Molecular Biology
- Cancer Research
- Cellular Signaling
Background:
- Oxidative stress and 4-hydroxynonenal (HNE) activate the Nuclear Factor Erythroid 2-Related Factor 2 (NRF2)/Kelch Like ECH Associated Protein 1 (KEAP1) pathway, vital for cellular redox homeostasis.
- The role of HNE and NRF2 in cancer initiation, progression, and therapy response is complex, involving interactions between cancer and stromal cells.
Purpose of the Study:
- To explore the epigenetic mechanisms regulating NRF2 transcription.
- To elucidate the role of NRF2 in cancer stem cells and therapy resistance.
- To discuss NRF2's involvement in tumor-associated inflammatory and stromal cell communication impacting therapy response.
Main Methods:
- Review of epigenetic mechanisms governing NRF2 promoter activity.
- Analysis of NRF2's role in cancer stem cells and therapy resistance.
- Examination of NRF2's cross-talk with tumor microenvironment components.
Main Results:
- Epigenetic regulation of NRF2 transcription involves promoter anatomy and chromatin permissiveness.
- NRF2 plays a significant role in cancer stem cell-mediated therapy resistance.
- NRF2 signaling influences communication between tumor-associated inflammatory and stromal cells, affecting therapeutic outcomes.
Conclusions:
- Epigenetic control of NRF2 is critical for its function in cancer.
- Targeting NRF2 pathways may offer strategies to overcome cancer therapy resistance.
- Understanding NRF2's role in tumor microenvironment interactions is key for developing effective cancer treatments.
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