Fig. 1

Gene and epigenetic regulations of KIT expression in GIST. KIT extracellular segment contains five immunoglobulin-like structural domains (D1-D5), D1-D2-D3 are stem cell factor (SCF) binding regions, and D4-D5 are important units for KIT dimer formation. In the absence of ligand stimulation, two adjacent KIT protein D4 structures remain independent due to charge repulsion. KIT mutations usually arise in the extracellular domains (exon 9), the juxtamembrane domain (exon 11) and in the kinase I and II domains (exons 13 and 17). The SCF binding to KIT and then changes the conformation of KIT and promote its dimerization, thereby activating tyrosine kinase activity in the intracellular segment by recruiting and phosphorylating substrates, thus forming signal transduction. But once KIT mutated, it disrupts its self-inhibition mechanism, resulting in continuous activation of signaling pathways such as Ras-Erk within the cell. FOXF1, ETV1 and HIC1 together form the core TF network in GIST binding enhancer and/or promoter and then promoting KIT expression. BRD4 (function as “readers”), HAND1 and BRAX1 positive regulate the core TF network. Transcription factor MITF and BIRC5 promote KIT transcription. MiRNA-20a, miRNA-17–92, miRNA200b-3p, miRNA-494, miRNA-148-3p are tumor suppressors downregulate KIT transcription and the majority of them directly bind to the 3’-UTR domain of relevant mRNA; the first three mentioned miRNAs can inhibit ETV1 mRNA levels, miRNA-494 can inhibit BIRC5 expression suggesting a negative feedback mechanism. SH3BP2 promotes the expression of mutant KIT by up-regulation of the expression of MITF and ETV1. FTO, functions as a “eraser”, promoting m6A demethylation increases the expression of KIT. Normal KIT chromosomal has CTCF insulator creating a topological boundary. Once CTCF insulator displaced by DNA methylation, allowing the super-enhancer to contact and induce KIT