Abstract
Within cells multiple related transcription factors targeting the same sequences may co-exist, leading to potential regulatory cooperativity, redundancy or competition. Yet the differential roles and biological functions of co-targeting transcription factors is poorly understood. In melanoma, three highly-related transcription factors are co-expressed: The mTORC1-regulated TFEB and TFE3, that are key effectors of a wide range of metabolic and microenvironmental cues; and MITF, that controls melanoma phenotypic identity. Here we reveal the functional specialization of MITF, TFE3 and TFEB and their impact on cancer progression. Notably, although all bind the same sequences, each regulates radically different and frequently opposing gene expression programs to coordinate differentiation, metabolic reprogramming, protein synthesis, and expression of immune modulators. The results uncover a hierarchical cascade in which microenvironmental stresses, including glucose limitation, lead MITF, TFEB and TFE3 to drive distinct biologically important transcription programs that underpin phenotypic transitions in cancer.