Keap1/Nrf2 pathway in kidney cancer: frequent methylation of KEAP1 gene promoter in clear renal cell carcinoma keap1/nrf2 pathway in kidney cancer:frequent methylation of keap1 gene promoter in clear renal cell carcinoma

The programmed death 1 receptor (PD-1) and its ligand (PD-L1) are key molecules of immune checkpoint mechanisms in cancer and actually represent one of the main targets of immunotherapy. The predictive and prognostic values of PD-L1 expression alone in cancer patients is currently under debate due to the methodological assessment of PD-L1 expression and its temporal variations. Better detailed studies about the molecular basis of immunotherapy biomarkers are necessary. Here we summarize the current knowledge of PD-L1 gene modifications at genetic and epigenetic levels in different tumors, thus highlighting their reported correlation with cellular processes and potential impact on patient outcomes.

Oxidative and electrophilic changes in cells are mainly coordinated by the KEAP1/NRF2 (Kelch‐like erythroid‐derived cap‐n‐collar homology‐ (ECH‐) associated protein‐1/nuclear factor (erythroid‐derived 2)‐like 2) axis. The physical interaction between these two proteins promotes the expression of several antioxidant defense genes in response to exogenous and endogenous insults. Recent studies demonstrated that KEAP1/NRF2 axis dysfunction is also strongly related to tumor progression and chemo‐ and radiotherapy resistance of cancer cells. In solid tumors, the KEAP1/NRF2 system is constitutively activated by the loss of KEAP1 or gain of NFE2L2 functions that leads to its nuclear accumulation and enhances the transcription of many cytoprotective genes. In addition to point mutations, epigenetic abnormalities, as aberrant promoter methylation, and microRNA (miRNA) and long noncoding RNA (lncRNA) deregulation were reported as emerging mechanisms of KEAP1/NRF2 axis modulation. This review will summarize the current knowledge about the epigenetic mechanisms that deregulate the KEAP1/NRF2 cascade in solid tumors and their potential usefulness as prognostic and predictive molecular markers.

The transcription factor Nrf2 (NF‐E2 related factor 2) is a master regulator of the cell antioxidant response associated with tumor growth and resistance to cytotoxic treatments. In particular, Nrf2 induces upregulation of cytoprotective genes by interacting with the closely situated AREs (Antioxidant Response Elements) in response to endogenous or exogenous stress stimuli and takes part to several oncogenic signaling pathways. Among these, the crosstalk with Notch pathway has been shown to enhance cytoprotection and maintenance of cellular homeostasis, tissue organization by modulating cell proliferation kinetics, and stem cell self‐renewal in several organs. The role of Notch and Nrf2 related pathways in tumorigenesis is highly variable and when they are both abnormally activated they can synergistically cause neoplastic proliferation by promoting cell survival, differentiation, invasion, and metastases. NFE2L2, KEAP1, and NOTCH genes family appear in the list of significantly mutated genes in tumors in both combined and individual sets, supporting the crucial role that the aberrant Nrf2‐Notch crosstalk might have in cancerogenesis. In this review, we summarize current knowledge about the alterations of Nrf2 and Notch pathways and their reciprocal transcriptional regulation throughout tumorigenesis and progression of lung tumors, supporting the potentiality of putative biomarkers and therapeutic targets.