21P - U2AF1 (S34F) mutation leads to altered global splicing patterns and dysregulation of cell cycle and mitosis

Date 15 April 2016
Event European Lung Cancer Conference 2016 (ELCC) 2016
Session Poster lunch
Topics Thoracic malignancies
Translational Research
Basic Principles in the Management and Treatment (of cancer)
Presenter Yeonjoo Jung
Citation Journal of Thoracic Oncology (2016) 11 (supplement 4): S57-S166. S1556-0864(16)X0004-4
Authors Y. Jung1, S. Kim2, C. Park2, Y. Jun2, S. Lee2, J. Kim2
  • 1Department Of Life Science And Ercsb (ewha Research Center For Systems Biology), Ewha Womans University, 03760 - Seoul/KR
  • 2Department Of Life Science And Ercsb (ewha Research Center For Systems Biology), Ewha Womans University, Seoul/KR

Abstract

Background

The U2AF1, also known as U2AF35, forms a heterodimeric splicing factor with U2AF2. In cancer, the recurrent somatic mutations in U2AF1 have been identified at least two different cancer types, acute myeloid leukemia and lung adenocarcinoma. The S34F-mutation in U2AF1 has been found frequently in lung adenocarcinoma, but the function of U2AF1-S34F mutants is not fully understood in lung cancer development. Specifically, it is not known whether the mutation represents the loss- or gain-of-function with regards to carcinogenesis.

Methods

We collected transcriptome data from the U2AF1-S34F-overexpressed or the U2AF1-depleted A549 cells. Alternatively spliced transcripts were compared with those from 8 patients with U2AF1-S34F mutation in lung adenocarcinoma (LUAD) from The Cancer Genome Atlas (TCGA). The Gene Ontology (GO) analysis was carried out subsequently for alternatively spliced genes. We also analyzed the cell cycle by flow cytometry and mitotic progression by confocal microscopy in U2AF1-S34F-overexpressed and U2AF1-depleted cells.

Results

Both overexpression of mutant U2AF1-S34F and knockdown by RNAi led to alternative splicing in large numbers of genes. Notably, numerous genes involved in regulation of cell cycle and mitosis were found. Consistently, both overexpression of mutant U2AF1-S34F and knockdown of U2AF1 led to G2M arrest as well as problems in mitotic progression. However, there was a very limited overlap in alternatively spliced genes between these two groups. In fact, integrating data from LUAD patients revealed that as far as cell cycle and mitosis are concerned, ectopic expression of mutant led to a splicing pattern similar to those seen from the lung cancer patients.

Conclusions

Based on our analysis of changes in splicing pattern, it is the expression of mutant U2AF1-S34F protein rather than the loss of a wild type allele that contributes carcinogenic development of lung adenocarcinoma.

Clinical trial identification

Legal entity responsible for the study

N/A

Funding

The National Research Foundation of Korea (NRF) funded by the Ministry of Science, ICT & Future Planning

Disclosure

All authors have declared no conflicts of interest.