The RNA-Binding Protein ESRP1 Modulates the Expression of RAC1b in Colorectal Cancer Cells

Abstract

RNA binding proteins are well recognized as critical regulators of tumorigenic processes through their capacity to modulate RNA biogenesis, including alternative splicing, RNA stability and mRNA translation. The RNA binding protein Epithelial Splicing Regulatory Protein 1 (ESRP1) can act as a tumor suppressor or promoter in a cell type- and disease context-dependent manner. We have previously shown that elevated expression of ESRP1 in colorectal cancer cells can drive tumor progression. To gain further insights into the pro-tumorigenic mechanism of action of ESRP1, we performed cDNA microarray analysis on two colorectal cells lines modulated for ESRP1 expression. Intriguingly, RAC1b was highly expressed, both at mRNA and protein levels, in ESRP1-overexpressing cells, while the opposite trend was observed in ESRP1-silenced CRC cells. Moreover, RAC1 and RAC1b mRNA co-immunoprecipitate with ESRP1 protein. Silencing of RAC1b expression significantly reduced the number of soft agar colonies formed by ESRP1-overexpressing cells, suggesting that ESRP1 acted, at least partially, through RAC1b in its tumor-promoting activities in CRC cells. Thus, our data provide molecular cues on targetable candidates in CRC cases with high ESRP1 expression.

RNA-binding protein transcripts as potential biomarkers for detecting Primary Sclerosing Cholangitis and for predicting its progression to Cholangiocarcinoma

“…To this regard, we and others have previously shown how too much or too little of an RBP can activate oncogenic pathways, albeit through different mechanisms, in colorectal cancer (CRC). In particular, over-expression of the RBP, Epithelial Splicing Regulatory protein 1 (ESRP1), which are the “splicing masterminds” of epithelial cells, led to the surge of a partial Epithelial-to-mesenchymal transition (EMT) status in CRC cells, as happens with the downregulation of its expression, seemingly through the context-dependent association of this RBP with different RNPs ( Fagoonee et al, 2017 ; Ala et al, 2020 ; Manco et al, 2021 ; Advani et al, 2023 ). Of late, dysregulation of RBPs were shown to modulate the responsiveness of tumor cells to chemotherapeutic drugs by binding specific sequences in the 3′-UTRs of target mRNAs to enhance or hinder mRNA translation; forming complexes with other proteins, including RBPs, within RNPs; promoting the formation of new splice variants; and prompting nuclear/cytoplasmic translocation ( Mir et al, 2022 ; Cen et al, 2023 ).…”