Abstract
Transcription factor EB (TFEB) represents an emerging player in cancer biology. Together with microphthalmia-associated transcription factor, transcription factor E3 and transcription factor EC, TFEB belongs to the microphthalmia family of bHLH-leucine zipper transcription factors that may be implicated in human melanomas, renal and pancreatic cancers. TFEB was originally described as being translocated in a juvenile subset of pediatric renal cell carcinoma; however, whole-genome sequencing reported that somatic mutations were sporadically found in many different cancers. Besides its oncogenic activity, TFEB controls the autophagy-lysosomal pathway by recognizing a recurrent motif present in the promoter regions of a set of genes that participate in lysosome biogenesis; furthermore, its dysregulation was found to have a crucial pathogenic role in different tumors by modulating the autophagy process. Other than regulating cancer cell-autonomous responses, recent findings indicate that TFEB participates in the regulation of cellular functions of the tumor microenvironment. Here, we review the emerging role of TFEB in regulating cancer cell behavior and choreographing tumor-microenvironment interaction. Recognizing TFEB as a hub of network of signals exchanged within the tumor between cancer and stroma cells provides a fresh perspective on the molecular principles of tumor self-organization, promising to reveal numerous new and potentially druggable vulnerabilities.
Highlights
In the last 15 years, transcription factors (TF) and enhancers are becoming emergent players in oncogenesis and cancer progression, with a bloom of new information focusing on molecular aberrations and altered regulatory functions resulting in pro-tumoral genetic landscapes
Abbreviations AMPK, AMP-activated kinase; Cyclin-Dependent Kinase (CDK), cyclin-dependent kinase; CLEAR, coordinated lysosomal expression and regulation; Epithelial-mesenchymal transition (EMT), epithelialmesenchymal transition; ERK, extracellular-signal-regulated kinase; GSK, glycogen synthase kinase; HLH, helix-loop-helix; MALAT, metastasis-associated lung adenocarcinoma transcript 1; MAP3K3, mitogen-activated protein kinase kinase kinase 3; MiT, microphthalmia; PK, protein kinase; Peroxisome proliferator-activated receptor (Ppar), peroxisome proliferator-activated receptor; Ppargc, Ppar gamma coactivator; Ras homolog enriched in brain’ (Rheb), Ras homolog enriched in brain; TF, transcription factor; Transcription factor EB (TFEB), transcription factor EB; TGF-b, transforming growth factor b; TME, tumor microenvironment
The most defined system phosphorylating TFEB and halting its nuclear translocation is represented by mTORC1 [20,21,23,25] and Rag GTPases, which determine the localization of mTORC1 and TFEB itself on the cytosolic surface of lysosomes [21,33,34,35]
Summary
In the last 15 years, transcription factors (TF) and enhancers are becoming emergent players in oncogenesis and cancer progression, with a bloom of new information focusing on molecular aberrations and altered regulatory functions resulting in pro-tumoral genetic landscapes. We illustrate the role of TFEB in tumor biology, envisaging that the control of its de-regulated activities observed in some cancers could be of therapeutic interest. TFEB belongs to the microphthalmia (MiT) family of basic helix-loop-helix (bHLH)-leucine zipper TF, which includes microphtalmia-associated TF (MITF), TFE3 and TFEC. It is considered a master regulator of lysosomal and autophagosomal biogenesis and represents a molecular tool to adapt cells to stress, including starvation and energy depletion. Recent findings clearly demonstrate wider regulatory activities encompassing metabolism, immunity, angiogenesis and inflammation, which are not necessarily connected with autophagy
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