PTBP1 drives c-Myc-dependent gastric cancer progression and stemness

Abstract

Background Gastric cancer (GC) tumorigenesis and treatment failure are caused by cancer stem cells. Polypyrimidine tract binding protein 1 (PTBP1) was shown to be involved in the development of embryonic stem cells and is now being considered as a therapeutic target for tumour progression and stem-cell characteristics. Methods PTBP1 expression in GC samples was detected using tissue microarrays. Proliferation, colony formation, spheroid formation and stem-cell analysis were used to examine PTBP1’s role in tumorigenesis and stem-cell maintenance. In AGS and HGC-27 cells with or without PTBP1 deficiency, ubiquitin-related protein expression and co-precipitation assays were performed. Results We identified that PTBP1 was aberrantly highly expressed and represented a novel prognostic factor in GC patients. PTBP1 maintained the tumorigenic activity and stem-cell characteristics of GC in vitro and in vivo. PTBP1 directly interacts with c-Myc and stabilises its protein levels by preventing its proteasomal degradation. This is mediated by upregulating the ubiquitin-specific proteases USP28 and limiting FBW7-mediated ubiquitination of c-Myc. Moreover, the depletion of PTBP1-caused tumour regression was significantly compromised by exogenous c-Myc expression. Conclusions By preserving the stability of c-Myc through the ubiquitin–proteasome pathway, the oncogene PTBP1 supports stem-cell-like phenotypes of GC and is involved in GC progression.

RAVER1 interconnects lethal EMT and miR/RISC activity by the control of alternative splicing

“…Positional rules guiding this PTBP-dependent modulation of splicing were recently demonstrated by a capture RIC-seq (CRIC-seq) method, which enriches RBPassociated RNA-RNA fragments (9). PTBP-modulated control of AS is frequently disturbed in cancer and deregulated expression of PTBPs is associated with adverse disease outcome in various malignancies (10)(11)(12). Elevated expression of PTBP1, the most abundant PTBP paralogue in most cancers, is associated with poor outcome in various solid cancers and associated with clinical properties suggesting roles of PTBPs in cancer progression (12).…”