INVESTIGATING ALTERNATIVE SPLICING REPROGRAMMING REGULATED BY THE E-CADHERIN/B-CATENIN AXIS

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.

Grantor dc:publisher

Università degli Studi di Milano

Year dc:date

2024

Author dc:creator

• MAESTRINI, GIORGIA

Contributors dc:contributor

• tutor: S. Polo ; co-tutor: C. Niño ; coordinatore: S. Minucci
• Nino
• Carlos
• G. Maestrini
• POLO, SIMONA LAURA ANNA
• MINUCCI, SAVERIO

• Settore BIO/10 - Biochimica

Statement dc:rights

• info:eu-repo/semantics/openAccess

Language dc:language

eng

Identifier

http://dx.doi.org/10.13130/maestrini-giorgia_phd2024-04-11
10.13130/maestrini-giorgia_phd2024-04-11

OAI identifier oai:identifier

oai:air.unimi.it:2434/1039311