YY1: Master regulator of metabolic reprogramming in cancer

Abstract

Metabolic reprogramming is a hallmark of cancer, enabling tumor cells to fulfill increased bioenergetic and biosynthetic demands for survival and proliferation. These adaptations arise directly from oncogenic mutations or indirectly via adaptive responses to nutrient scarcity. In addition to supporting survival and biomass production, these metabolic shifts are closely associated with changes in gene expression, cellular differentiation, and the tumor microenvironment, thereby contributing to tumorigenesis and progression. Importantly, the recognition of metabolic dysregulation as a hallmark of malignancy revealed novel avenues for therapeutic intervention, as disrupting these pathways may impair energy generation and biosynthetic processes essential for tumor proliferation. In this review, we integrate data indicating that the transcription factor Yin yang 1 (YY1) is a central regulator of oncogenic metabolic reprogramming. Yin yang 2 (YY2) is a paralog of YY1 and performs distinct role in metabolism and redox regulation. Mechanistically, YY1 enhances aerobic glycolysis by diverting glycolytic flux toward lactate production. Furthermore, it modulates hepatic lipid homeostasis via direct transcriptional control of lipogenic enzymes and crosstalk with nutrient-sensing signaling cascades. Additionally, YY1 rewires amino acid metabolism to fuel tumorigenesis by supplying macromolecules and enabling epigenetic remodeling. Collectively, these findings highlight the equilibrium between YY1 and its paralog YY2 in sustaining redox homeostasis and tumor progression while positioning YY1 as a metabolic checkpoint that dynamically regulates these processes. Understanding these pathways will support development of YY1-directed inhibitors and combinatorial therapies to modulate metabolic reprogramming in cancer.