Emerging roles of the MiT/TFE factors in cancer

The microphthalmia/transcription factor E (MiT/TFE) transcription factors are master regulators of autophagy and lysosome biogenesis. MiT/TFE factors are subject to extensive regulation through post-translational modifications that control their stability, nuclear–cytoplasmic translocation, and activity. Much of MiT/TFE regulation occurs at the lysosome and involves the mechanistic target of rapamycin complex 1 kinase, the folliculin (FLCN) and FLCN-interacting protein 1/2 complex, and the Rag guanosine triphosphatases. Genomic alterations and post-transcriptional dysregulation of MiT/TFE factors are contributing factors to the progression of several cancers. MiT/TFE factors engage in an increasingly complex interplay with other tumor-associated transcription factors to regulate metabolic and stress adaptation. The microphthalmia/transcription factor E (MiT/TFE) transcription factors (TFs; TFEB, TFE3, MITF, and TFEC) play a central role in cellular catabolism and quality control and are subject to extensive layers of regulation that influence their localization, stability, and activity. Recent studies have highlighted a broader role for these TFs in driving diverse stress-adaptation pathways, which manifest in a context- and tissue-dependent manner. Several human cancers upregulate the MiT/TFE factors to survive extreme fluctuations in nutrients, energy, and pharmacological challenges. Emerging data suggest that reduced activity of the MiT/TFE factors can also promote tumorigenesis. Here, we outline recent findings relating to novel mechanisms of regulation and activity of MiT/TFE proteins across some of the most aggressive human cancers. The microphthalmia/transcription factor E (MiT/TFE) transcription factors (TFs; TFEB, TFE3, MITF, and TFEC) play a central role in cellular catabolism and quality control and are subject to extensive layers of regulation that influence their localization, stability, and activity. Recent studies have highlighted a broader role for these TFs in driving diverse stress-adaptation pathways, which manifest in a context- and tissue-dependent manner. Several human cancers upregulate the MiT/TFE factors to survive extreme fluctuations in nutrients, energy, and pharmacological challenges. Emerging data suggest that reduced activity of the MiT/TFE factors can also promote tumorigenesis. Here, we outline recent findings relating to novel mechanisms of regulation and activity of MiT/TFE proteins across some of the most aggressive human cancers.