Abstract
Stem cell factor (mouse: Kitl, human: KITLG) and insulin-like growth factor-1 (IGF1), acting via KIT and IGF1 receptor (IGF1R), respectively, are critical for the development and integrity of several tissues. Autocrine/paracrine KITLG-KIT and IGF1-IGF1R signaling are also activated in several cancers including gastrointestinal stromal tumors (GIST), the most common sarcoma. In murine gastric muscles, IGF1 promotes Kitl-dependent development of interstitial cells of Cajal (ICC), the non-neoplastic counterpart of GIST, suggesting cooperation between these pathways. Here, we report a novel mechanism linking IGF1-IGF1R and KITLG-KIT signaling in both normal and neoplastic cells. In murine gastric muscles, the microenvironment for ICC and GIST, human hepatic stellate cells (LX-2), a model for cancer niches, and GIST cells, IGF1 stimulated Kitl/KITLG protein and mRNA expression and promoter activity by activating several signaling pathways including AKT-mediated glycogen synthase kinase-3β inhibition (GSK3i). GSK3i alone also stimulated Kitl/KITLG expression without activating mitogenic pathways. Both IGF1 and GSK3i induced chromatin-level changes favoring transcriptional activation at the Kitl promoter including increased histone H3/H4 acetylation and H3 lysine (K) 4 methylation, reduced H3K9 and H3K27 methylation and reduced occupancy by the H3K27 methyltransferase EZH2. By pharmacological or RNA interference-mediated inhibition of chromatin modifiers we demonstrated that these changes have the predicted impact on KITLG expression. KITLG knock-down and immunoneutralization inhibited the proliferation of GIST cells expressing wild-type KIT, signifying oncogenic autocrine/paracrine KITLG-KIT signaling. We conclude that membrane-to-nucleus signaling involving GSK3i establishes a previously unrecognized link between the IGF1-IGF1R and KITLG-KIT pathways, which is active in both physiologic and oncogenic contexts and can be exploited for therapeutic purposes.
Highlights
Stem cell factor is the natural ligand of the type 3 receptor tyrosine kinase (RTK) KIT
Our findings indicate that insulin-like growth factor-1 (IGF1) stimulates KITLG transcription by inducing coordinated chromatin modifications in part via glycogen synthase kinase (GSK)-3β inhibition
To investigate the role of autocrine/paracrine KITLG–KIT signaling in gastrointestinal stromal tumors (GIST) proliferation, we examined the effect of KITLG immunoneutralization and RNA interference (RNAi)-mediated knock-down in GIST cells expressing or lacking WT KIT
Summary
Stem cell factor (mouse: Kitl; human: KITLG) is the natural ligand of the type 3 receptor tyrosine kinase (RTK) KIT. A 220-aminoacid isoform, which only generates secreted peptide at a slow rate, is produced from an alternatively spliced transcript lacking exon 6 (“membrane-bound” isoform; Kitl220/KITLG220) [3]. In other cancers including the majority (75-80%) of gastrointestinal stromal tumors (GIST), which originate from cells of the ICC lineage [4,5], KIT signaling is constitutively active due to oncogenic mutations [6]. Since imatinib preferentially targets mutant receptors [6], reduced drug responsiveness [9,10] and aggressive GIST behavior [11] may reflect activation of WT KIT expressed in the majority of GIST by KITLG originating from the circulation, the tumor cells, or their niche [9,11,12,13]. Direct evidence of KITLG-driven GIST cell proliferation is lacking
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