RNA binding protein EIF2S2 promotes tumorigenesis and progression by regulating MYC-mediated inhibition via FHIT-related enhancers

Abstract RNA-binding proteins (RBPs) play fundamental roles in cancer, however, we are still lack of knowledge about to what extent the RBPs were dysregulated, as well as perturbed signaling pathways in cancer. Here, we integrated analysis of multi-dimensional data across >10,000 cancer patients and >1,000 cell lines. We identified a top candidate RBP, Eukaryotic translation Initiation Factor 2 subunit Beta (EIF2S2). EIF2S2 is highly expressed in tumors and is associated with malignant features as well as patient prognosis. Functional assays performed in cancer cells revealed that EIF2S2 promotes the cancer cell proliferation, migration and invasion in vitro as well as the tumor growth and metastasis in vivo. Mechanistic investigations further demonstrated that EIF2S2 promotes tumorigenesis and progression by directly binding to a long noncoding RNA, LINC01600, which physically interacts with the MYC protein and increases its stability. Interestingly, we revealed that EIF2S2-LINC01600-MYC axis can activate the Wnt/β-catenin pathway by inhibiting the activity of FHIT-related enhancers and FHIT expression. Finally, EIF2S2 knockdown combined with oxaliplatin treatment could be a potential combination therapy in cancer. Our integrated analysis provided detailed knowledge of the function of EIF2S2-LINC01600-MYC axis, which will facilitate the development of rational combination therapies for cancer.