ETV1 is a member of the ETS family of transcription factors, already known oncogenic drivers in Ewing sarcoma, prostate cancer and gastrointestinal stromal tumors, but not in gliomas.
In this study, we explored the potential agents targeting ETV1 in GISTs by uploading an ETV1 knockout gene signature of GIST cell lines to the pattern‑matching software 'Connectivity Map'.
Three significantly differential circRNAs (circ_0069765, circ_0084097, and circ_0079471) and their host genes (KIT, PLAT, and ETV1) were also verified in 68 pairs of GISTs and adjacent normal gastrointestinal tissues by qRT-PCR.
Further, FOXF1 colocalizes with ETV1 at enhancers and functions as a pioneer factor that regulates the ETV1-dependent GIST lineage-specific transcriptome through modulation of the local chromatin context, including chromatin accessibility, enhancer maintenance, and ETV1 binding.
A new study now shows that the forkhead box (FOX) family transcription factor FOXF1 not only is an upstream regulator of ETV1 and hence ICC/GIST lineage-specific gene transcription, but also functions as lineage-specific pioneer factor with an active role in chromatin rearrangement to facilitate ETV1 binding and transcriptional activity.<i>Cancer Discov; 8(2); 146-9.
Recently, in situ hybridization (ISH) for E26 transformation-specific sequence variant 1 (ETV1) mRNA was introduced as a useful marker to diagnose GIST.
Here, we present a model in which the ETV1 promoter is used to specifically and inducibly drive Cre recombinase in ICC as a strategy to study GIST pathogenesis.
These advances have characterized ETV1 as an essential interstitial cell of Cajal-GIST transcription factor in oncogenic KIT signaling pathways, and have characterized the biologically distinct subgroup of succinate dehydrogenase deficient GIST, which are particularly common in young adults.
Notably, ETV1 was positive in 15 of 26 (58 %) KIT-negative GISTs and even positive in 2 cases of GISTnegative for KIT and DOG1, whereas only 6 (5 %) non-GIST mesenchymal GI tumors expressed ETV1.
MiR-17/20a/222 overexpression in GIST cell lines severely inhibited cell proliferation, affected cell cycle progression, induced apoptosis and strongly downregulated protein and--to a lesser extent--mRNA levels of their predicted target genes KIT and ETV1.
We propose that GIST arises from ICCs with high levels of endogenous ETV1 expression that, when coupled with an activating KIT mutation, drives an oncogenic ETS transcriptional program.