MiT/TFE transcription factors directly upregulate RagD, which activates mTORC1 to support tumor growth.

  • Major finding: MiT/TFE transcription factors directly upregulate RagD, which activates mTORC1 to support tumor growth.

  • Concept: RagD depletion suppresses tumor cell proliferation in vitro and melanoma xenograft growth in vivo.

  • Impact: Deregulation of the MiT/TFE–RagD–mTORC1 regulatory feedback circuit may promote tumor growth.

The nutrient-sensing mTORC1 complex promotes protein synthesis and inhibits catabolic pathways. It integrates environmental signals to control cell survival and proliferation, and mTORC1 signaling is often deregulated in cancer. mTORC1 phosphorylates the MiT/TFE transcription factors (TFEB, TFE3, TFEC, and MITF), which regulate lysosomal and melanosomal biogenesis and autophagy, promoting cytoplasmic retention to suppress their activity. During starvation, mTORC1 inhibition promotes activation of TFEB and TFE3. Di Malta and colleagues hypothesized that the MiT/TFE transcription factors might also regulate mTORC1 activity in a feedback loop. Consistent with this hypothesis, overexpression of TFEB and TFE3 with leucine or arginine was sufficient to activate mTORC1. In contrast, liver-specific depletion of TFEB reduced protein synthesis and mTORC1 signaling in vivo. TFEB-mediated activation of mTORC1 did not require essential autophagy genes, suggesting an autophagy-independent mechanism. Instead, TFEB upregulated the guanosine triphosphatase (GTPase) RagD. Chromatin immunoprecipitation showed that RagD is a direct target of TFEB, and deletion of the TFEB response element in the RagD promoter suppressed RagD expression and mTORC1 activation upon amino acid stimulation. mTORC1 activity could be rescued by RagD overexpression, altogether indicating that MiT/TFE transcription factors regulate mTORC1 activity via RagD. Further, TFEB-mediated upregulation of RagD promoted amino acid–induced recruitment of mTORC1 to the lysosome. The MiT/TFE transcription factors are overexpressed in a variety of cancers, and tumor cells from a patient with renal cell carcinoma with a chromosomal translocation involving TFE3 displayed increased RagD expression and mTORC1 signaling. Depletion of TFE3 or RagD suppressed tumor cell proliferation and mTORC1 signaling. Further, in melanoma xenografts with elevated RagD expression and mTORC1 activity, RagD depletion suppressed tumor growth. These findings define a mechanism by which MiT/TFE transcription factors control mTORC1 activity to promote tumor growth.

Di Malta C, Siciliano D, Calcagni A, Monfregola J, Punzi S, Pastore N, et al. Transcriptional activation of RagD GTPase controls mTORC1 and promotes cancer growth. Science 2017;356:1188–92.

©2017 American Association for Cancer Research.
2017
American Association for Cancer Research.