Phospho-IWS1-dependent U2AF2 splicing is cell-cycle-regulated, promotes proliferation and predicts poor prognosis of EGFR-mutant lung adenocarcinoma

Abstract Our previous studies have shown that IWS1 is a phosphorylation target of AKT in human lung cancer. RNA-seq studies using lung adenocarcinoma cells lacking IWS1, identified an exon 2 deficient splice variant of U2AF2, affecting U2AF65 RS domain and its binding with Prp19. This depends on pho...

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Published inbioRxiv
Main Authors Laliotis, Georgios I, Chavdoula, Evangelia, Paraskevopoulou, Maria D, Kaba, Abdul D, Alessandro La Ferlita, Singh, Satishkumar, Vollter Anastas, Alaimo, Salvatore, Orlacchio, Arturo, Nair, Keith A, Taraslia, Vasiliki, Vlachos, Ioannis, Capece, Marina, Hatzigeorgiou, Artemis, Palmieri, Dario, Tsatsanis, Christos, Sehgal, Lalit, Carbone, David P, Coppola, Vincenzo, Tsichlis, Philip N
Format Paper
LanguageEnglish
Published Cold Spring Harbor Cold Spring Harbor Laboratory Press 10.03.2021
Subjects
Adenocarcinoma
AKT protein
Alternative splicing
Cell cycle
Cell proliferation
Epidermal growth factor receptors
Epigenetics
Information processing
Kinases
Lung cancer
Medical prognosis
Metastases
Methylation
Mutants
Phosphorylation
RNA processing
Therapeutic targets
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Summary:Abstract Our previous studies have shown that IWS1 is a phosphorylation target of AKT in human lung cancer. RNA-seq studies using lung adenocarcinoma cells lacking IWS1, identified an exon 2 deficient splice variant of U2AF2, affecting U2AF65 RS domain and its binding with Prp19. This depends on phosphorylated IWS1 and the assembly of LEDGF/SRSF1 splicing complexes, via H3K36 trimethylation through the cell cycle. Inhibition of the pathway results in Sororin downregulation, a target and regulator of ERK, G2/M phase arrest, impaired cell proliferation and tumor growth, more pronounced in EGFR mutant cells. Analysis of lung adenocarcinoma samples revealed that the IWS1 phosphorylation pathway correlates with advanced stage, relapse, metastasis and poor survival in patients harboring EGFR mutations. This work highlights the instrumental role of the AKT/p-IWS1 axis to the epigenetic regulation of RNA processing and oncogenic signals, proposing it as a drug target in EGFR mutant lung adenocarcinoma. Competing Interest Statement The authors have declared no competing interest. Footnotes * ↵16 These authors jointly supervised this work : Philip N. Tsichlis (Philip.tsichlis{at}osumc.edu) (lead contact) and Georgios I. Laliotis (glaliot7{at}gmail.com) * https://data.mendeley.com/datasets/y82yx8gfkj/4 * https://data.mendeley.com/datasets/ts44bfg45k/1
DOI:10.1101/2020.07.14.195297