An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth

Adam S. Adler, Mark L. McCleland, Sharon Yee, Murat Yaylaoglu, Sofia Hussain, Ely Cosino, Gabriel Quinones, Zora Modrusan, Somasekar Seshagiri, Eric Torres, Vivek S. Chopra, Benjamin Haley, Zemin Zhang, Elizabeth M. Blackwood, Mallika Singh, Melissa R. Junttila, Jean-Philippe Stephan, Jinfeng Liu, Gregoire Pau, Eric R. FearonZhaoshi Jiang, Ron Firestein

Research output: Contribution to journalArticleResearchpeer-review

43 Citations (Scopus)

Abstract

The spliceosome machinery is composed of multimeric protein complexes that generate a diverse repertoire of mRNA through coordinated splicing of heteronuclear RNAs. While somatic mutations in spliceosome components have been discovered in several cancer types, the molecular bases and consequences of spliceosome aberrations in cancer are poorly understood. Here we report for the first time that PRPF6, a member of the trisnRNP (small ribonucleoprotein) spliceosome complex, drives cancer proliferation by preferential splicing of genes associated with growth regulation. Inhibition of PRPF6 and other tri-snRNP complex proteins, but not other snRNP spliceosome complexes, selectively abrogated growth in cancer cells with high tri-snRNP levels. Highresolution transcriptome analyses revealed that reduced PRPF6 alters the constitutive and alternative splicing of a discrete number of genes, including an oncogenic isoform of the ZAK kinase. These findings implicate an essential role for PRPF6 in cancer via splicing of distinct growth-related gene products.

Original languageEnglish
Pages (from-to)1068-1084
Number of pages17
JournalGenes and Development
Volume28
Issue number10
DOIs
Publication statusPublished - 15 May 2014
Externally publishedYes

Keywords

  • Colon cancer
  • PRPF6
  • RNAi
  • Spliceosome
  • Tri-snRNP

Cite this

Adler, Adam S. ; McCleland, Mark L. ; Yee, Sharon ; Yaylaoglu, Murat ; Hussain, Sofia ; Cosino, Ely ; Quinones, Gabriel ; Modrusan, Zora ; Seshagiri, Somasekar ; Torres, Eric ; Chopra, Vivek S. ; Haley, Benjamin ; Zhang, Zemin ; Blackwood, Elizabeth M. ; Singh, Mallika ; Junttila, Melissa R. ; Stephan, Jean-Philippe ; Liu, Jinfeng ; Pau, Gregoire ; Fearon, Eric R. ; Jiang, Zhaoshi ; Firestein, Ron. / An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth. In: Genes and Development. 2014 ; Vol. 28, No. 10. pp. 1068-1084.
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abstract = "The spliceosome machinery is composed of multimeric protein complexes that generate a diverse repertoire of mRNA through coordinated splicing of heteronuclear RNAs. While somatic mutations in spliceosome components have been discovered in several cancer types, the molecular bases and consequences of spliceosome aberrations in cancer are poorly understood. Here we report for the first time that PRPF6, a member of the trisnRNP (small ribonucleoprotein) spliceosome complex, drives cancer proliferation by preferential splicing of genes associated with growth regulation. Inhibition of PRPF6 and other tri-snRNP complex proteins, but not other snRNP spliceosome complexes, selectively abrogated growth in cancer cells with high tri-snRNP levels. Highresolution transcriptome analyses revealed that reduced PRPF6 alters the constitutive and alternative splicing of a discrete number of genes, including an oncogenic isoform of the ZAK kinase. These findings implicate an essential role for PRPF6 in cancer via splicing of distinct growth-related gene products.",
keywords = "Colon cancer, PRPF6, RNAi, Spliceosome, Tri-snRNP",
author = "Adler, {Adam S.} and McCleland, {Mark L.} and Sharon Yee and Murat Yaylaoglu and Sofia Hussain and Ely Cosino and Gabriel Quinones and Zora Modrusan and Somasekar Seshagiri and Eric Torres and Chopra, {Vivek S.} and Benjamin Haley and Zemin Zhang and Blackwood, {Elizabeth M.} and Mallika Singh and Junttila, {Melissa R.} and Jean-Philippe Stephan and Jinfeng Liu and Gregoire Pau and Fearon, {Eric R.} and Zhaoshi Jiang and Ron Firestein",
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Adler, AS, McCleland, ML, Yee, S, Yaylaoglu, M, Hussain, S, Cosino, E, Quinones, G, Modrusan, Z, Seshagiri, S, Torres, E, Chopra, VS, Haley, B, Zhang, Z, Blackwood, EM, Singh, M, Junttila, MR, Stephan, J-P, Liu, J, Pau, G, Fearon, ER, Jiang, Z & Firestein, R 2014, 'An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth', Genes and Development, vol. 28, no. 10, pp. 1068-1084. https://doi.org/10.1101/gad.237206.113

An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth. / Adler, Adam S.; McCleland, Mark L.; Yee, Sharon; Yaylaoglu, Murat; Hussain, Sofia; Cosino, Ely; Quinones, Gabriel; Modrusan, Zora; Seshagiri, Somasekar; Torres, Eric; Chopra, Vivek S.; Haley, Benjamin; Zhang, Zemin; Blackwood, Elizabeth M.; Singh, Mallika; Junttila, Melissa R.; Stephan, Jean-Philippe; Liu, Jinfeng; Pau, Gregoire; Fearon, Eric R.; Jiang, Zhaoshi; Firestein, Ron.

In: Genes and Development, Vol. 28, No. 10, 15.05.2014, p. 1068-1084.

Research output: Contribution to journalArticleResearchpeer-review

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AU - Hussain, Sofia

AU - Cosino, Ely

AU - Quinones, Gabriel

AU - Modrusan, Zora

AU - Seshagiri, Somasekar

AU - Torres, Eric

AU - Chopra, Vivek S.

AU - Haley, Benjamin

AU - Zhang, Zemin

AU - Blackwood, Elizabeth M.

AU - Singh, Mallika

AU - Junttila, Melissa R.

AU - Stephan, Jean-Philippe

AU - Liu, Jinfeng

AU - Pau, Gregoire

AU - Fearon, Eric R.

AU - Jiang, Zhaoshi

AU - Firestein, Ron

PY - 2014/5/15

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KW - RNAi

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Adler AS, McCleland ML, Yee S, Yaylaoglu M, Hussain S, Cosino E et al. An integrative analysis of colon cancer identifies an essential function for PRPF6 in tumor growth. Genes and Development. 2014 May 15;28(10):1068-1084. https://doi.org/10.1101/gad.237206.113