INVESTIGATING ALTERNATIVE SPLICING REPROGRAMMING REGULATED BY THE E-CADHERIN/B-CATENIN AXIS
type: CreativeWork
description: Alternative splicing (AS) is vital for proteome flexibility and its aberrations are key drivers of cancer progression. We identified an alternatively spliced exon cassette in myosin VI, an actin motor protein. In healthy epithelial tissues like the ovary and intestine, this exon cassette is carefully regulated, producing the myosin VIlong isoform involved in endocytic functions. However, in epithelial tumors like colorectal adenocarcinoma (COAD), aberrant splicing leads to the expression of the myosin VIshort isoform, promoting tumor-cell migration. Using the Caco-2 cell line, capable of modulating isoform expression under different conditions, we uncovered the molecular mechanism behind this dysregulation, pinpointing E-cadherin and β-catenin as central players in myosin VI AS regulation. β-catenin's nuclear translocation induces myosin VIshort expression, while its depletion rescues myosin VIlong. Furthermore, we uncovered β-catenin's broader involvement in AS oncogenic reprogramming, impacting nearly 500 AS events. Among them, we characterized the α6A isoform of the integrin receptor as upregulated by β-catenin hyperactivation, potentially contributing to CRC invasiveness. To uncover the molecular mechanism that leads to β-catenin-mediated AS reprogramming we specifically blocked the transcriptional activity of β-catenin by overexpressing a dominant negative form of its transcriptional partner and we found it contributes to regulate AS. Among the different deregulated genes, only the splicing factor RBM47 well fit as a downstream β-catenin target as its depletion causes the concordant modulation of the AS events tested, while a concomitant β-catenin depletion restores the control phenotype. This study elucidates β-catenin's novel role in AS reprogramming during epithelial maturation and intestinal tumor development.
abstract: Alternative splicing (AS) is vital for proteome flexibility and its aberrations are key drivers of cancer progression. We identified an alternatively spliced exon cassette in myosin VI, an actin motor protein. In healthy epithelial tissues like the ovary and intestine, this exon cassette is carefully regulated, producing the myosin VIlong isoform involved in endocytic functions. However, in epithelial tumors like colorectal adenocarcinoma (COAD), aberrant splicing leads to the expression of the myosin VIshort isoform, promoting tumor-cell migration. Using the Caco-2 cell line, capable of modulating isoform expression under different conditions, we uncovered the molecular mechanism behind this dysregulation, pinpointing E-cadherin and β-catenin as central players in myosin VI AS regulation. β-catenin's nuclear translocation induces myosin VIshort expression, while its depletion rescues myosin VIlong. Furthermore, we uncovered β-catenin's broader involvement in AS oncogenic reprogramming, impacting nearly 500 AS events. Among them, we characterized the α6A isoform of the integrin receptor as upregulated by β-catenin hyperactivation, potentially contributing to CRC invasiveness. To uncover the molecular mechanism that leads to β-catenin-mediated AS reprogramming we specifically blocked the transcriptional activity of β-catenin by overexpressing a dominant negative form of its transcriptional partner and we found it contributes to regulate AS. Among the different deregulated genes, only the splicing factor RBM47 well fit as a downstream β-catenin target as its depletion causes the concordant modulation of the AS events tested, while a concomitant β-catenin depletion restores the control phenotype. This study elucidates β-catenin's novel role in AS reprogramming during epithelial maturation and intestinal tumor development.
author: MAESTRINI, GIORGIA
language: eng
keywords: Settore BIO/10 - Biochimica
date published: 2024-04-11
date modified: 2026-07-27T20:19:12Z
provider: Università degli Studi di Milano
publisher: Networked Digital Library of Theses and Dissertations
type: WebPage
source organization: Università degli Studi di Milano

PropertyValue
property ID: Handle
value: https://hdl.handle.net/2434/1039311

PropertyValue
property ID: DOI
value: 10.13130/maestrini-giorgia_phd2024-04-11