Fig. 4: Critical roles of enhancer reprogramming in cancer.

Unlocking Unlimited Proliferation: MYC, as a principal regulator of cell proliferation, undergoes enhancer reprogramming widely across various tumors, driving cancer transformation and forming a shared paradigm of foundational enhancer reprogramming in cancer. Additionally, enhancer reprogramming disrupts normal growth inhibition signals by regulating the expression of cell cycle factors (e.g., MYC, CCNA2), enabling cancer cells to sustain continuous division. It also promotes tumor growth by upregulating genes like MDM2, which suppress p53 function. Enhancer reprogramming collaborates with signaling pathways such as WNT and NOTCH to sustain infinite cancer cell proliferation by forming core regulatory circuits (CRCs). For instance, in liver cancer, WNT/β-catenin signaling activates key enhancers, driving the upregulation of the DLK1/DIO3 genomic locus and promoting tumor growth and progression. Invading metabolic networks: Enhancer reprogramming disrupts metabolic pathways in tumor cells, driving significant changes in energy production, biosynthesis, and gene regulation. Enhancers upregulate glucose transporters (e.g., GLUT1) and glycolytic enzymes (e.g., HK2, LDHA), promoting the Warburg effect and supporting anabolic metabolism. They also amplify lipid synthesis by regulating factors like SREBF1 and SREBF2, meeting the high demand for fatty acids and cholesterol in cancer cells. Similarly, amino acid metabolism is enhanced through CRC-regulated genes (e.g., LAT1), promoting tumor growth and survival. Enhancer-driven NAD metabolism reprogramming supports energy production and redox balance, further fueling cancer cell proliferation. Moreover, metabolites from these metabolic pathways, such as acetyl-CoA and S-adenosylmethionine, serve as substrates for histone and DNA modifications, establishing a feedback loop between metabolism and epigenetic remodeling to sustain tumor progression. Activating metastasis: Enhancer reprogramming plays a crucial role throughout various stages of tumor metastasis by driving the epithelial–mesenchymal transition (EMT), modulating the tumor microenvironment, and enabling immune evasion and colonization at distant sites. It activates key transcription factors (e.g., Snail, Twist) and signaling pathways (e.g., TGF-β, WNT/β-catenin), enhancing cancer cell migration, invasion, and adaptation to new microenvironments. During metastasis, enhancer-driven transcriptional reprogramming promotes organ-specific gene expression programs, such as FOXA1-mediated liver metastasis in pancreatic cancer. Additionally, epigenetic memory maintained by enhancers allows tumor cells to adapt and proliferate rapidly in distant organs (such as MET). Driving drug resistance: Enhancer reprogramming plays a pivotal role in cancer chemotherapy resistance through mechanisms such as upregulation of drug resistance genes, enhanced DNA repair, metabolic reprogramming, and lineage plasticity. (Created with BioRender.com).