A Regulatory Axis between Epithelial Splicing Regulatory Proteins and Estrogen Receptor α Modulates the Alternative Transcriptome of Luminal Breast Cancer
Autor: | Jamal Elhasnaoui, Giulio Ferrero, Valentina Miano, Lorenzo Franchitti, Isabella Tarulli, Lucia Coscujuela Tarrero, Santina Cutrupi, Michele De Bortoli |
---|---|
Přispěvatelé: | Elhasnaoui, Jamal [0000-0001-9311-0417], Ferrero, Giulio [0000-0002-4580-0680], Miano, Valentina [0000-0002-0260-5885], Tarulli, Isabella [0000-0003-4807-081X], Coscujuela Tarrero, Lucia [0000-0001-5889-6100], Cutrupi, Santina [0000-0002-2358-5852], Apollo - University of Cambridge Repository |
Rok vydání: | 2022 |
Předmět: |
Epithelial-Mesenchymal Transition
Rac1b Breast Neoplasms Catalysis Inorganic Chemistry breast cancer ESRP1 ESRP2 alternative splicing EMT splicing signature Rac1 Cell Line Tumor Humans Physical and Theoretical Chemistry Molecular Biology Spectroscopy Organic Chemistry Estrogen Receptor alpha RNA-Binding Proteins General Medicine Computer Science Applications Gene Expression Regulation Neoplastic Alternative Splicing Female Transcriptome Transcription Factors |
Zdroj: | International Journal of Molecular Sciences; Volume 23; Issue 14; Pages: 7835 |
Popis: | Epithelial splicing regulatory proteins 1 and 2 (ESRP1/2) control the splicing pattern during epithelial to mesenchymal transition (EMT) in a physiological context and in cancer, including breast cancer (BC). Here, we report that ESRP1, but not ESRP2, is overexpressed in luminal BCs of patients with poor prognosis and correlates with estrogen receptor α (ERα) levels. Analysis of ERα genome-binding profiles in cell lines and primary breast tumors showed its binding in the proximity of ESRP1 and ESRP2 genes, whose expression is strongly decreased by ERα silencing in hormone-deprived conditions. The combined knock-down of ESRP1/2 in MCF-7 cells followed by RNA-Seq, revealed the dysregulation of 754 genes, with a widespread alteration of alternative splicing events (ASEs) of genes involved in cell signaling, metabolism, cell growth, and EMT. Functional network analysis of ASEs correlated with ESRP1/2 expression in ERα+ BCs showed RAC1 as the hub node in the protein–protein interactions altered by ESRP1/2 silencing. The comparison of ERα- and ESRP-modulated ASEs revealed 63 commonly regulated events, including 27 detected in primary BCs and endocrine-resistant cell lines. Our data support a functional implication of the ERα-ESRP1/2 axis in the onset and progression of BC by controlling the splicing patterns of related genes. |
Databáze: | OpenAIRE |
Externí odkaz: |