Gastric cancer is the third leading cause of cancer-related death worldwide. The regulatory mechanisms underlying gastric cancer cell proliferation are largely unclear. Here, we show that the transcription factor GFI1 is associated with advanced clinical gastric cancer progression and promoted gastric cancer cell proliferation partially through inhibition of gastrokine-2 (GKN2) transcription. GFI1 was a degrading substrate of FBXW7, whose loss was observed in gastric cancer. Mechanistically, GSK3b-mediated GFI1 S94/S98 phosphorylation triggered its interaction with FBXW7, resulting in SCFFBXW7-mediated ubiquitination and degradation. A nondegradable GFI1 S94A/S98A mutant was more potent in driving gastric cancer cell proliferation and tumorigenesis than wild-type GFI1. Overall, this study reveals the oncogenic role of GFI1 in gastric cancer and provides mechanistic insights into the tumor suppressor function of FBXW7. Significance: These findings demonstrate the oncogenic role of the transcription factor GFI1 and the tumor suppressive function of FBXW7 in gastric cancer.

Living organisms have developed a complex signaling system to sense diverse growth signals and co-ordinate intracellular bioprocesses, so that they survive in various conditions. Since organisms are often exposed to environmental and genomic threats which cause DNA damages, DNA damage response (DDR) and repair systems are important for maintenance of genome stability and integrity. A line of evidences has demonstrated that there is tight crosstalk between growth signaling pathways and DDR systems. In this review, we give a brief overview of recent reports dissecting the interaction between signaling pathways and DDR at molecular level, which may further expand the knowledge of the signaling network and provide clues for disease therapy.

<p>Figure S1-GFI1 promotes GC cell proliferation and suppresses GKN2 expression.Figure S2-FBXW7 governs GFI1 stability.Figure S3-GSK3β destabilizes GFI1 and negatively regulates GFI1 expression. Figure S4-Spectrum of peptide containing GFI1 S94 phosphorylation.</p>