Establishment of a TGFβ-Induced Post-Transcriptional EMT Gene Signature

Abstract

A major challenge in the clinical management of human cancers is to accurately stratify patients according to risk and likelihood of a favorable response. Stratification is confounded by significant phenotypic heterogeneity in some tumor types, often without obvious criteria for subdivision. Despite intensive transcriptional array analyses, the identity and validation of cancer specific ‘signature genes’ remains elusive, partially because the transcriptome does not mirror the proteome. The simplification associated with transcriptomic profiling does not take into consideration changes in the relative expression among transcripts that arise due to post-transcriptional regulatory events. We have previously shown that TGFβ post-transcriptionally regulates epithelial-mesenchymal transition (EMT) by causing increased expression of two transcripts, Dab2 and ILEI, by modulating hnRNP E1 phosphorylation. Using a genome-wide combinatorial approach involving expression profiling and RIP-Chip analysis, we have identified a cohort of translationally regulated mRNAs that are induced during TGFβ-mediated EMT. Coordinated translational regulation by hnRNP E1 constitutes a post-transcriptional regulon inhibiting the expression of related EMT-facilitating genes, thus enabling the cell to rapidly and coordinately regulate multiple EMT-facilitating genes.

HOTAIR Long Noncoding RNA Promotes Gastric Cancer Metastasis through Suppression of Poly r(C)-Binding Protein (PCBP) 1

“…In the second study, PCBP1 was shown to downregulate production of the prometastatic PRL-3 phosphatase (29). Thus it might be possible that downregulation of PCBP1 dictates mesenchymal cell formation in a context-dependent fashion, as observed by us in the current study and the others (26)(27)(28)(29).…”

“…In one of those, a transcript-selective translational regulatory pathway was described in which a ribonucleoprotein (mRNP) complex, consisting of PCBP1, silences translation of mRNAs that are involved in mediating EMT and metastatic progression (26). It was shown that TGF-b activates a kinase cascade terminating in the phosphorylation of PCBP1 by isoform-specific stimulation of protein kinase Bb/Akt2, inducing the release of the mRNP complex from the 3 0 -UTR element, in turn resulting in the reversal of translational silencing and increased expression of transcripts that mediates EMT (26)(27)(28). In the second study, PCBP1 was shown to downregulate production of the prometastatic PRL-3 phosphatase (29).…”

Transforming Growth Factor β Regulates P-Body Formation through Induction of the mRNA Decay Factor Tristetraprolin

“…Interestingly, TGF-␤ signaling promotes phosphorylation of hnRNP E1 and its release from the mRNA, allowing eEF1A1-mediated translational elongation to proceed (66,67). While this conserved 3= UTR element appears to be distinct to AU-rich elements (68), these findings further highlight the functional contribution of TGF-␤ in posttranscriptional regulation.…”

Membrane-organizing protein moesin controls Treg differentiation and antitumor immunity via TGF-β signaling

“…Although TGF-β plays important roles during iTreg generation, little is known about the post-transcriptional mechanisms by which it exerts some of its effects on T cells. Previous results from a combined polyribosome profiling and Affymetrix array identified selective EMT genes that are translationally upregulated by TGF-β (14). Since TGF-β is important for the generation of iTregs, we hypothesized that in naive CD4 + T cells, hnRNP E1 selectively binds to and stalls the translation of EMT genes, which are also involved in iTreg differentiation (Supplemental Figure 1A; supplemental material available online with this article; https:// doi.org/10.1172/JCI89281DS1).…”