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Simple Summary: The stress-responsive transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2) directs cellular metabolic processes that can have diverse effects in the context of cancer. This review addresses how NRF2 and its negative regulator KEAP1 (Kelch-like ECH-associated protein 1) collectively modulate and respond to metabolism. We highlight NRF2-regulated processes relevant to the antioxidant system, cellular proliferation, and survival, including metabolism of amino acids, lipids, NADPH (reduced nicotinamide adenine dinucleotide phosphate), iron, and heme. We also review the stabilization of NRF2 by electrophiles, metabolites, and autophagy. Finally, we discuss topics that warrant further investigation into the KEAP1/NRF2 pathway's role in tumor progression. The transcription factor NRF2 (nuclear factor-erythroid 2 p45-related factor 2 or NFE2L2) plays a critical role in response to cellular stress. Following an oxidative insult, NRF2 orchestrates an antioxidant program, leading to increased glutathione levels and decreased reactive oxygen species (ROS). Mounting evidence now implicates the ability of NRF2 to modulate metabolic processes, particularly those at the interface between antioxidant processes and cellular proliferation. Notably, NRF2 regulates the pentose phosphate pathway, NADPH production, glutaminolysis, lipid and amino acid metabolism, many of which are hijacked by cancer cells to promote proliferation and survival. Moreover, deregulation of metabolic processes in both normal and cancer-based physiology can stabilize NRF2. We will discuss how perturbation of metabolic pathways, including the tricarboxylic acid (TCA) cycle, glycolysis, and autophagy can lead to NRF2 stabilization, and how NRF2-regulated metabolism helps cells deal with these metabolic stresses. Finally, we will discuss how the negative regulator of NRF2, Kelch-like ECH-associated protein 1 (KEAP1), may play a role in metabolism through NRF2 transcription-independent mechanisms. Collectively, this review will address the interplay between the NRF2/KEAP1 complex and metabolic processes. [ABSTRACT FROM AUTHOR]

Significance: The stress responsive transcription factor nuclear factor erythroid 2 p45-related factor 2, or NRF2, regulates the expression of many cytoprotective enzymes to mitigate oxidative stress under physiological conditions. NRF2 is activated in response to oxidative stress, growth factor signaling, and changes in nutrient status. In addition, somatic mutations that disrupt the interaction between NRF2 and its negative regulator Kelch-like erythroid cell-derived protein with CNC homology (ECH)-associated 1 (KEAP1) commonly occur in cancer and are thought to promote tumorigenesis. Recent Advances: While it is well established that aberrant NRF2 activation results in enhanced antioxidant capacity in cancer cells, recent exciting findings demonstrate a role for NRF2-mediated metabolic deregulation that supports cancer cell proliferation. Critical Issues: In this review, we describe how the NRF2-KEAP1 signaling pathway is altered in cancer, how NRF2 is regulated by changes in cellular metabolism, and how NRF2 reprograms cellular metabolism to support proliferation. Future Directions: Future studies will delineate the NRF2-regulated processes critical for metabolic adaptation to nutrient availability, cellular proliferation, and tumorigenesis. Antioxid. Redox Signal. 00, 000–000. [ABSTRACT FROM AUTHOR]

Fascin is a pro-metastatic actin-bundling protein that is upregulated in all metastatic carcinomas. Fascin promotes cancer cell migration and invasion by facilitating membrane protrusions, such as filopodia and invadopodia. Aerobic glycolysis is a key feature of cancer metabolism and provides critical intermediate metabolites for tumor growth. Here, we report that fascin increases glycolysis in lung cancer to promote tumor growth and metastasis. Fascin promotes glycolytic flux by increasing the expression and activities of phosphofructose-kinases 1 and 2 (PFK1 and 2). Fascin mediates glycolytic functions via activation of yes-associated protein 1 (YAP1) through its canonical actin-bundling activity by promoting the binding of YAP1 to a TEAD1/4 binding motif located 30 bp upstream of the PFKFB3 transcription start site to activate its transcription. Examination of the TCGA database suggests that the fascin-YAP1-PFKFB3 axis is likely conserved across different types of cancers. Importantly, pharmacological inhibitors of fascin suppressed YAP1-PFKFB3 signaling and glycolysis in cancer cell lines, organoid cultures, and xenograft metastasis models. Taken together, our data reveal that the glycolytic function of fascin is essential for the promotion of lung cancer growth and metabolism, and suggest that pharmacological inhibitors of fascin may be used to reprogram cancer metabolism in lung and potentially other cancers with fascin upregulation. [ABSTRACT FROM AUTHOR]