Fig. 8: Alternative splicing product of FIR/PUF60 gene, FIRΔexon2, contributes to E-cadherin suppression through post-transcriptional regulation of BRG1.
From: Post-transcriptional regulation of BRG1 by FIRΔexon2 in gastric cancer
FIRΔexon2 is an alternative splicing variant form of FIR. FIRΔexon2 is expressed in cancers when FIR pre-mRNA is disturbed by an autocatalytic mechanism through inhibiting the FIR-SAP155 splicing complex9. Ribosomal proteins, hnRNPs, splicing-related factors, poly(A) binding proteins, mRNA-binding proteins, tRNA, or DEAD box proteins (DDX) were commonly co-immunoprecipitated with FIR or FIRΔexon2, indicating that both FIR and FIRΔexon2 participate in post-transcriptional or translational processes. FIRΔexon2, but not FIR, reduced the level of H3K27ac at the BRG1 promotor. The protein expression of BRG1 was decreased by FIRΔexon2 overexpression, suggesting that FIRΔexon2 partly affects nucleosome remodeling. FIRΔexon2 potentially inhibits the accession of substrate proteins of FBW7 to its degron pocket (c.f. Fig. 6). BK697 is a small molecular weight chemical containing a WD-like domain that inhibits FIR/FIRΔexon2. Snai1 is a transcriptional repressor of E-cadherin. Together, the suppression of E-cadherin by BK697 was at least partly post-transcriptional, including inhibiting FBW7 function. A novel chemical inhibitor of FIR/PUF60 and its splicing variants were revealed to target EMT through FBW7 and E-cadherin in this study. Three-dimensional crystal structure analysis revealed that the U2AF-homology motif (UHM) of FIR or FIRΔexon2 interacted with the WD-like motif in the degron pocket of FBW7. Therefore, the interaction between FIRΔexon2 and FBW7 inhibits FBW7-mediated proteasomal degradation of BRG1 and Snai1. BK697 is a novel, low molecular weight compound containing a WD-like domain targeting FIRΔexon2. Overall, our study suggests that FIRΔexon2-mediated suppression of E-cadherin via the FBW7/BRG1/Snai1 axis prevents EMT and invasion in gastric cancer.
