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.
Highlights
It has been proposed that excessive production of reactive oxygen species (ROS) and numerous cellular redox adaptation responses are involved in cancer initiation, progression, and drug resistance [1,2,3]
Was shown that Bach 1 contributes to glycolysis and increased production of Adenosine TriPhosphate (ATP) through its binding to Hexokinase 2 (Hex 2) and Glyceraldehyde-3-Phosphate Dehydrogenase (Gapdh) promoters [88]. All these data indicate the complexity of signaling pathways which include Nuclear Factor Erythroid 2-Related Factor 2 (NRF2), its targets and its competitors, and are developed in a specific cellular background. They further indicate that the roles of NRF2 in cancer must be considered from many aspects, and that additional data are necessary to clarify whether selective targeting of NRF2 has the potential to be implemented in the field of cancer therapy
The research on the epigenetic regulation of NRF2 will certainly prosper in the future
Summary
It has been proposed that excessive production of reactive oxygen species (ROS) and numerous cellular redox adaptation responses are involved in cancer initiation, progression, and drug resistance [1,2,3]. These events contribute to ROS production and lead to the occurrence of a vicious circle of carcinogenic oxidative stress [15] Under such circumstances, ROS serve cancer as pro-growth signaling molecules, triggering a self-catalyzed chain reaction process of lipid peroxidation of polyunsaturated fatty acids (PUFAs), in particular. In response to an excessive ROS production, cancer cells develop several transcriptional programs which rely on transcription factors/their binding partners that contain redox-responsive cysteines These programs include members of the Forkhead Box Protein O3 (FOXO) family, Hypoxia Inducible Factors (HIFs), Kelch-Like ECH-Associated Protein 1 (KEAP1) with NRF2 and the Tumori protein P53 (TP53) tumor suppressor-related transcriptional program [41,42,43,44]. We focus on molecular aspects of NRF2 functioning, with respect to its structure and modes of activation, associated with several aspects of oxidative stress and therapy response of cancer
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