Molecules and Cells

  • 제41권8호
  • /
  • Pages.733-741
  • /
  • 2018
  • /
  • 1016-8478(pISSN)
  • /
  • 0219-1032(eISSN)
한국분자세포생물학회 (Korean Society for Molecular and Cellular Biology)
권호 표지
DOI QR코드

DOI QR Code

Integrative Profiling of Alternative Splicing Induced by U2AF1 S34F Mutation in Lung Adenocarcinoma Reveals a Mechanistic Link to Mitotic Stress

  • Kim, Suyeon (Ewha Research Center for Systems Biology (ERCSB)) ;
  • Park, Charny (Research Institute, National Cancer Center) ;
  • Jun, Yukyung (Ewha Research Center for Systems Biology (ERCSB)) ;
  • Lee, Sanghyuk (Ewha Research Center for Systems Biology (ERCSB)) ;
  • Jung, Yeonjoo (Ewha Research Center for Systems Biology (ERCSB)) ;
  • Kim, Jaesang (Ewha Research Center for Systems Biology (ERCSB))
  • 투고 : 2018.04.22
  • 심사 : 2018.05.30
  • 발행 : 2018.08.31
PDF 다운로드
⟨ 이전 논문 다음 논문 ⟩

초록

Mutations in spliceosome components have been implicated in carcinogenesis of various types of cancer. One of the most frequently found is U2AF1 S34F missense mutation. Functional analyses of this mutation have been largely limited to hematological malignancies although the mutation is also frequently seen in other cancer types including lung adenocarcinoma (LUAD). We examined the impact of knockdown (KD) of wild type (wt) U2AF1 and ectopic expression of two splice variant S34F mutant proteins in terms of alternative splicing (AS) pattern and cell cycle progression in A549 lung cancer cells. We demonstrate that induction of distinct AS events and disruption of mitosis at distinct sub-stages result from KD and ectopic expression of the mutant proteins. Importantly, when compared with the splicing pattern seen in LUAD patients with U2AF1 S34F mutation, ectopic expression of S34F mutants but not KD was shown to result in common AS events in several genes involved in cell cycle progression. Our study thus points to an active role of U2AF1 S34F mutant protein in inducing cell cycle dysregulation and mitotic stress. In addition, alternatively spliced genes which we describe here may represent novel potential markers of lung cancer development.

키워드

참고문헌

  1. Brooks, A.N., Choi, P.S., de Waal, L., Sharifnia, T., Imielinski, M., Saksena, G., Pedamallu, C.S., Sivachenko, A., Rosenberg, M., Chmielecki, J., et al. (2014). A pan-cancer analysis of transcriptome changes associated with somatic mutations in U2AF1 reveals commonly altered splicing events. PLoS One 9, e87361. https://doi.org/10.1371/journal.pone.0087361
  2. Damm, F., Kosmider, O., Gelsi-Boyer, V., Renneville, A., Carbuccia, N., Hidalgo-Curtis, C., Della Valle, V., Couronne, L., Scourzic, L., Chesnais, V., et al. (2012). Mutations affecting mRNA splicing define distinct clinical phenotypes and correlate with patient outcome in myelodysplastic syndromes. Blood 119, 3211-3218. https://doi.org/10.1182/blood-2011-12-400994
  3. Duijf, P.H. and Benezra, R. (2013). The cancer biology of wholechromosome instability. Oncogene 32, 4727-4736. https://doi.org/10.1038/onc.2012.616
  4. Fu, Y., Masuda, A., Ito, M., Shinmi, J. and Ohno, K. (2011). AGdependent 3-splice sites are predisposed to aberrant splicing due to a mutation at the first nucleotide of an exon. Nucleic Acids Res. 39, 4396-4404. https://doi.org/10.1093/nar/gkr026
  5. Futreal, P.A., Coin, L., Marshall, M., Down, T., Hubbard, T., Wooster, R., Rahman, N. and Stratton, M.R. (2004). A census of human cancer genes. Nat. Rev. Cancer 4, 177-183. https://doi.org/10.1038/nrc1299
  6. Graubert, T.A., Shen, D., Ding, L., Okeyo-Owuor, T., Lunn, C.L., Shao, J., Krysiak, K., Harris, C.C., Koboldt, D.C., Larson, D.E., et al. (2012). Recurrent mutations in the U2AF1 splicing factor in myelodysplastic syndromes. Nat. Genet. 44, 53-57. https://doi.org/10.1038/ng.1031
  7. Ilagan, J.O., Ramakrishnan, A., Hayes, B., Murphy, M.E., Zebari, A.S., Bradley, P. and Bradley, R.K. (2015). U2AF1 mutations alter splice site recognition in hematological malignancies. Genome Res. 25, 14-26. https://doi.org/10.1101/gr.181016.114
  8. Imielinski, M., Berger, A.H., Hammerman, P.S., Hernandez, B., Pugh, T.J., Hodis, E., Cho, J., Suh, J., Capelletti, M., Sivachenko, A., et al. (2012). Mapping the hallmarks of lung adenocarcinoma with massively parallel sequencing. Cell 150, 1107-1120. https://doi.org/10.1016/j.cell.2012.08.029
  9. Jung, Y., Jun, Y., Lee, H.Y., Kim, S., Jung, Y., Keum, J., Lee, Y.S., Cho, Y.B., Lee, S. and Kim, J. (2015). Characterization of SLC22A18 as a tumor suppressor and novel biomarker in colorectal cancer. Oncotarget 6, 25368-25380.
  10. Kim, J., Lo, L., Dormand, E. and Anderson, D.J. (2003). SOX10 maintains multipotency and inhibits neuronal differentiation of neural crest stem cells. Neuron 38, 17-31. https://doi.org/10.1016/S0896-6273(03)00163-6
  11. Makishima, H., Visconte, V., Sakaguchi, H., Jankowska, A.M., Abu Kar, S., Jerez, A., Przychodzen, B., Bupathi, M., Guinta, K., Afable, M.G., et al. (2012). Mutations in the spliceosome machinery, a novel and ubiquitous pathway in leukemogenesis. Blood 119, 3203-3210. https://doi.org/10.1182/blood-2011-12-399774
  12. Network, T.C.G.A.R. (2014). Comprehensive molecular profiling of lung adenocarcinoma. Nature 511, 543-550. https://doi.org/10.1038/nature13385
  13. Pacheco, T.R., Moita, L.F., Gomes, A.Q., Hacohen, N. and Carmo-Fonseca, M. (2006). RNA interference knockdown of hU2AF35 impairs cell cycle progression and modulates alternative splicing of Cdc25 transcripts. Mol. Biol. Cell 17, 4187-4199. https://doi.org/10.1091/mbc.e06-01-0036
  14. Park, S.M., Ou, J., Chamberlain, L., Simone, T.M., Yang, H., Virbasius, C.M., Ali, A.M., Zhu, L.J., Mukherjee, S., Raza, A., et al. (2016). U2AF35(S34F) Promotes transformation by directing aberrant ATG7 Pre-mRNA 3' end formation. Mol. Cell 62, 479-490. https://doi.org/10.1016/j.molcel.2016.04.011
  15. Przychodzen, B., Jerez, A., Guinta, K., Sekeres, M.A., Padgett, R., Maciejewski, J.P. and Makishima, H. (2013). Patterns of missplicing due to somatic U2AF1 mutations in myeloid neoplasms. Blood 122, 999-1006. https://doi.org/10.1182/blood-2013-01-480970
  16. Qian, J., Yao, D.M., Lin, J., Qian, W., Wang, C.Z., Chai, H.Y., Yang, J., Li, Y., Deng, Z.Q., Ma, J.C., et al. (2012). U2AF1 mutations in Chinese patients with acute myeloid leukemia and myelodysplastic syndrome. PLoS One 7, e45760. https://doi.org/10.1371/journal.pone.0045760
  17. Roschke, A.V. and Rozenblum, E. (2013). Multi-layered cancer chromosomal instability phenotype. Front Oncol. 3, 302.
  18. Shirai, C.L., Ley, J.N., White, B.S., Kim, S., Tibbitts, J., Shao, J., Ndonwi, M., Wadugu, B., Duncavage, E.J., Okeyo-Owuor, T., et al. (2015). Mutant U2AF1 expression alters hmatopoiesis and pre-mRNA splicing in vivo. Cancer Cell 27, 631-643. https://doi.org/10.1016/j.ccell.2015.04.008
  19. Thol, F., Kade, S., Schlarmann, C., Loffeld, P., Morgan, M., Krauter, J., Wlodarski, M.W., Kolking, B., Wichmann, M., Gorlich, K., et al. (2012). Frequency and prognostic impact of mutations in SRSF2, U2AF1, and ZRSR2 in patients with myelodysplastic syndromes. Blood 119, 3578-3584. https://doi.org/10.1182/blood-2011-12-399337
  20. Yoshida, K., Sanada, M., Shiraishi, Y., Nowak, D., Nagata, Y., Yamamoto, R., Sato, Y., Sato-Otsubo, A., Kon, A., Nagasaki, M., et al. (2011). Frequent pathway mutations of splicing machinery in myelodysplasia. Nature 478, 64-69. https://doi.org/10.1038/nature10496

피인용 문헌

  1. Splicing Machinery is Dysregulated in Pituitary Neuroendocrine Tumors and is Associated with Aggressiveness Features vol.11, pp.10, 2018, https://doi.org/10.3390/cancers11101439
  2. Elucidation of the aberrant 3′ splice site selection by cancer-associated mutations on the U2AF1 vol.11, pp.1, 2018, https://doi.org/10.1038/s41467-020-18559-6
  3. Proneural and mesenchymal glioma stem cells display major differences in splicing and lncRNA profiles vol.5, pp.1, 2018, https://doi.org/10.1038/s41525-019-0108-5
  4. The GENDULF algorithm: mining transcriptomics to uncover modifier genes for monogenic diseases vol.16, pp.12, 2020, https://doi.org/10.15252/msb.20209701
  5. CtIP-mediated alternative mRNA splicing fine-tunes the DNA damage response vol.27, pp.3, 2018, https://doi.org/10.1261/rna.078519.120