Deregulated transcription factors in cancer cell metabolisms and reprogramming

Abstract

Metabolic reprogramming is an important cancer hallmark that plays a key role in cancer malignancies and therapy resistance. Cancer cells reprogram the metabolic pathways to generate not only energy and building blocks but also produce numerous key signaling metabolites to impact signaling and epigenetic/transcriptional regulation for cancer cell proliferation and survival. A deeper understanding of the mechanisms by which metabolic reprogramming is regulated in cancer may provide potential new strategies for cancer targeting. Recent studies suggest that deregulated transcription factors have been observed in various human cancers and significantly impact metabolism and signaling in cancer. In this review, we highlight the key transcription factors that are involved in metabolic control, dissect the crosstalk between signaling and transcription factors in metabolic reprogramming, and offer therapeutic strategies targeting deregulated transcription factors for cancer treatment.

Keywords: Cancer treatment; Cell metabolism; Metabolic reprogramming; Signaling metabolites; Transcription factors.

Fig. 1.

The metabolic reprogramming distinctly occurs in cancer cells compared to normal cells. Normal cells depend on mitochondrial oxidative phosphorylation for glucose metabolism (right panel). In contrast, cancer cells (left panel) convert glucose to lactate in cytoplasm for ATP synthesis. In addition, cancer cells increase their glucose and glutamine uptake to generate more metabolic intermediates to support anabolic pathways for amino acid, nucleotide and lipid biosynthesis.

Fig. 2.

The one-carbon (1C) metabolism regulates the synthesis of purine, amino acids, and phospholipids to maintain the redox homeostasis and rapid cell growth. Cancer cells enhance the biosynthesis of amino acid serine and glycine. The amino acids are used as donors of one carbon unit, the 1C meta- bolism transfers this carbon unit for the biosynthesis of various metabolic outputs, such as nucleotides and redox homeostasis by folate and methio- nine cycles.

Fig. 3.

Dysregulated transcription factors impact cancer cell metabolism and reprogramming. (A) Myc and HIF1α regulate the expression of diverse metabolic enzymes. The green arrow indicated the Myc-upregulated enzymes (red) and transporters (blue). The enzymes elevated by Myc and HIF-1 were indicated by the blue arrow. (B) p53 and NRF2 regulate the expression of diverse metabolic enzymes. The green arrow indicates the p53 affected enzymes and transporters. The enzymes elevated by NRF2 were indicated by the black arrow. Inhibition is shown by Blunt arrow (┴), whereas activation is indicated by sharp arrow (→). Other transcription factors, such as chREBP1, SERBP1, and HIF1, are shown in blue.

Fig. 3.

Dysregulated transcription factors impact cancer cell metabolism and reprogramming. (A) Myc and HIF1α regulate the expression of diverse metabolic enzymes. The green arrow indicated the Myc-upregulated enzymes (red) and transporters (blue). The enzymes elevated by Myc and HIF-1 were indicated by the blue arrow. (B) p53 and NRF2 regulate the expression of diverse metabolic enzymes. The green arrow indicates the p53 affected enzymes and transporters. The enzymes elevated by NRF2 were indicated by the black arrow. Inhibition is shown by Blunt arrow (┴), whereas activation is indicated by sharp arrow (→). Other transcription factors, such as chREBP1, SERBP1, and HIF1, are shown in blue.

Fig. 4.

The crosstalk between transcriptional factors, signaling pathways and signaling metabolites regulates metabolic reprogramming. Tumor cells displayed dysregulated numerous transcription factors, which crosstalk with multiple signaling pathways to orchestrate distinct metabolic processes, thus facilitating cancer cell survival and cancer progression. The crosstalk between transcription factors indicated by the double headed arrows and enzymes are shown in red.