The MiTF/TFE Family of Transcription Factors: Master Regulators of Organelle Signaling, Metabolism, and Stress Adaptation

Abstract The microphthalmia family (MITF, TFEB, TFE3, and TFEC) of transcription factors is emerging as global regulators of cancer cell survival and energy metabolism, both through the promotion of lysosomal genes as well as newly characterized targets, such as oxidative metabolism and the oxidative stress response. In addition, MiT/TFE factors can regulate lysosomal signaling, which includes the mTORC1 and Wnt/β-catenin pathways, which are both substantial contributors to oncogenic signaling. This review describes recent discoveries in MiT/TFE research and how they impact multiple cancer subtypes. Furthermore, the literature relating to TFE-fusion proteins in cancers and the potential mechanisms through which these genomic rearrangements promote tumorigenesis is reviewed. Likewise, the emerging function of the Folliculin (FLCN) tumor suppressor in negatively regulating the MiT/TFE family and how loss of this pathway promotes cancer is examined. Recent reports are also presented that relate to the role of MiT/TFE–driven lysosomal biogenesis in sustaining cancer cell metabolism and signaling in nutrient-limiting conditions. Finally, a discussion is provided on the future directions and unanswered questions in the field. In summary, the research surrounding the MiT/TFE family indicates that these transcription factors are promising therapeutic targets and biomarkers for cancers that thrive in stressful niches. Mol Cancer Res; 15(12); 1637–43. ©2017 AACR.