Regulation of epithelial-mesenchymal transition and metastasis by TGF-β, P-bodies, and autophagy

Abstract

Processing bodies (P-bodies) are ribonucleoprotein complexes involved in post-transcriptional mRNA metabolism that accumulate in cells exposed to various stress stimuli. The treatment of mammary epithelial cells with transforming growth factor-beta (TGF-β), triggers epithelial-mesenchymal transition (EMT), and induces the formation of P-bodies. Ectopic expression of the transcription factor TWIST, which stimulates EMT downstream of the TGF-β receptor, also promotes P-body formation. Removal of TGF-β from treated cells results in the clearance of P-bodies by a process that is blocked by inhibitors of autophagy. Activators of autophagy enhance P-body clearance and block EMT. Blockage of P-body formation by disruption of the gene for DDX6, a protein essential for P-body assembly, blocks EMT and prevents tumor cell metastasis in vivo. These studies suggest critical roles for P-body formation and autophagy in transitions of cancer cells between epithelial and mesenchymal phenotypes and help explain how autophagy functions to promote or suppress tumor cell growth during different stages of tumorigenesis.

Spleen Tyrosine Kinase–Mediated Autophagy Is Required for Epithelial–Mesenchymal Plasticity and Metastasis in Breast Cancer

“…Mesenchymal cells also have an increased capacity to persist in the presence of chemotherapy (4,35,36). Our previous studies and our data herein are consistent with the notion that autophagy drives the MET process and efficient progression to macroscopic tumor formation (15). Our findings are strongly supported by recent studies indicating autophagy facilitates a dormant-to-proliferative switch by tumor cells within the lungs (16).…”

“…We have recently demonstrated that induction of EMT by TGFb induces the formation of cytoplasmic RNA-processing complexes called P-bodies, and clearance of P-bodies through autophagy is required for reversal of EMT (15). On the basis of our previous identification of a role for SYK in promoting stress granule clearance through autophagy and our identification of multiple P-body proteins as SYK substrates, we next sought to assess a role for SYK in P-body formation and clearance (11,27).…”

“…4C). Normal murine mammary gland (NMuMG) cells are highly responsive to TGFb-induced EMT, and form robust P-bodies during this process (15). Therefore, we treated control and SYKoverexpressing NMuMG cells with TGFb1 for 48 hours to induce P-body formation.…”

“…P-bodies are dynamic cytoplasmic foci that contain mRNAs, miRNAs, and mRNA-binding proteins involved in translation repression, mRNA degradation, and miRNA-mediated silencing. We recently established that P-bodies form during the onset of EMT and are removed during mesenchymal-epithelial transition (MET) by the process of autophagy (15). Similar to EMT, the role of autophagy in tumorigenesis is dynamic and highly context-dependent.…”

P-bodies are sites of rapid RNA decay during the neural crest epithelial—mesenchymal transition

“…In both development and disease, post-transcriptional regulation and, in particular, RNA turnover are key mechanisms by which cells are able to quickly alter their transcriptomic landscape and transit between cell states (Chen and Shyu, 2017;Hardy et al, 2017;Lou et al, 2015). The process of RNA decay is highly conserved across eukaryotes and mediated by multiple mRNA turnover pathways (Parker and Song, 2004).…”