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RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer.

Wolfe AL, Singh K, Zhong Y, Drewe P, Rajasekhar VK, Sanghvi VR, Mavrakis KJ, Jiang M, Roderick JE, Van der Meulen J, Schatz JH, Rodrigo CM, Zhao C, Rondou P, de Stanchina E, Teruya-Feldstein J, Kelliher MA, Speleman F, Porco JA, Pelletier J, Rätsch G, Wendel HG - Nature (2014)

Bottom Line: Accordingly, inhibition of eIF4A with silvestrol has powerful therapeutic effects against murine and human leukaemic cells in vitro and in vivo.Notably, among the most eIF4A-dependent and silvestrol-sensitive transcripts are a number of oncogenes, superenhancer-associated transcription factors, and epigenetic regulators.Hence, the 5' UTRs of select cancer genes harbour a targetable requirement for the eIF4A RNA helicase.

View Article: PubMed Central - PubMed

Affiliation: 1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Weill Cornell Graduate School of Medical Sciences, New York, New York 10065, USA [3].

ABSTRACT
The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of silvestrol and related compounds. For example, eIF4A promotes T-cell acute lymphoblastic leukaemia development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with silvestrol has powerful therapeutic effects against murine and human leukaemic cells in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5' untranslated region (UTR) sequences such as the 12-nucleotide guanine quartet (CGG)4 motif that can form RNA G-quadruplex structures. Notably, among the most eIF4A-dependent and silvestrol-sensitive transcripts are a number of oncogenes, superenhancer-associated transcription factors, and epigenetic regulators. Hence, the 5' UTRs of select cancer genes harbour a targetable requirement for the eIF4A RNA helicase.

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Related in: MedlinePlus

Silvestrol-sensitive transcriptsa) Distribution of ribosomal footprints for the indicated genes, n = 2 biological replicates. Silvestrol: Red; Vehicle: black; purple dots: 9-mer motifs; blue dots 12-mer motif; b) Gene ontology classification for genes in TE down group with G-quadruplex, 12-mer and 9-mer motif; c) Venn diagram illustrating the overlap between TE and/or rDiff genes and reported super-enhancers in T-ALL cell lines34.
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Figure 12: Silvestrol-sensitive transcriptsa) Distribution of ribosomal footprints for the indicated genes, n = 2 biological replicates. Silvestrol: Red; Vehicle: black; purple dots: 9-mer motifs; blue dots 12-mer motif; b) Gene ontology classification for genes in TE down group with G-quadruplex, 12-mer and 9-mer motif; c) Venn diagram illustrating the overlap between TE and/or rDiff genes and reported super-enhancers in T-ALL cell lines34.

Mentions: The Silvestrol sensitive transcripts (TE down and rDiff gene lists) include many genes with known roles in T-ALL (Figure 5a/b). The individual RF distribution graphs (normalized for mean RF count and gene length) illustrate recurrent patterns and also variations (Extended Data Fig. 7a). For example, the MYC, MDM2, and RUNX1 transcripts harbour multiple motifs in their 5′UTRs that correspond to peaks in RF density, while housekeeping genes show no changes in RF profiles. Gene ontology reveals a preponderance of transcription factors and oncogenes, but also some tumour suppressors (Extended Data Fig. 7b). Further, we note a significant enrichment of “super-enhancer”-associated genes34 - mostly transcription factors like NOTCH1, MYC, MYB, ETS1 and others (Figure 5c, Extended Data Fig. 7c, Suppl. Table 6).


RNA G-quadruplexes cause eIF4A-dependent oncogene translation in cancer.

Wolfe AL, Singh K, Zhong Y, Drewe P, Rajasekhar VK, Sanghvi VR, Mavrakis KJ, Jiang M, Roderick JE, Van der Meulen J, Schatz JH, Rodrigo CM, Zhao C, Rondou P, de Stanchina E, Teruya-Feldstein J, Kelliher MA, Speleman F, Porco JA, Pelletier J, Rätsch G, Wendel HG - Nature (2014)

Silvestrol-sensitive transcriptsa) Distribution of ribosomal footprints for the indicated genes, n = 2 biological replicates. Silvestrol: Red; Vehicle: black; purple dots: 9-mer motifs; blue dots 12-mer motif; b) Gene ontology classification for genes in TE down group with G-quadruplex, 12-mer and 9-mer motif; c) Venn diagram illustrating the overlap between TE and/or rDiff genes and reported super-enhancers in T-ALL cell lines34.
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4492470&req=5

Figure 12: Silvestrol-sensitive transcriptsa) Distribution of ribosomal footprints for the indicated genes, n = 2 biological replicates. Silvestrol: Red; Vehicle: black; purple dots: 9-mer motifs; blue dots 12-mer motif; b) Gene ontology classification for genes in TE down group with G-quadruplex, 12-mer and 9-mer motif; c) Venn diagram illustrating the overlap between TE and/or rDiff genes and reported super-enhancers in T-ALL cell lines34.
Mentions: The Silvestrol sensitive transcripts (TE down and rDiff gene lists) include many genes with known roles in T-ALL (Figure 5a/b). The individual RF distribution graphs (normalized for mean RF count and gene length) illustrate recurrent patterns and also variations (Extended Data Fig. 7a). For example, the MYC, MDM2, and RUNX1 transcripts harbour multiple motifs in their 5′UTRs that correspond to peaks in RF density, while housekeeping genes show no changes in RF profiles. Gene ontology reveals a preponderance of transcription factors and oncogenes, but also some tumour suppressors (Extended Data Fig. 7b). Further, we note a significant enrichment of “super-enhancer”-associated genes34 - mostly transcription factors like NOTCH1, MYC, MYB, ETS1 and others (Figure 5c, Extended Data Fig. 7c, Suppl. Table 6).

Bottom Line: Accordingly, inhibition of eIF4A with silvestrol has powerful therapeutic effects against murine and human leukaemic cells in vitro and in vivo.Notably, among the most eIF4A-dependent and silvestrol-sensitive transcripts are a number of oncogenes, superenhancer-associated transcription factors, and epigenetic regulators.Hence, the 5' UTRs of select cancer genes harbour a targetable requirement for the eIF4A RNA helicase.

View Article: PubMed Central - PubMed

Affiliation: 1] Cancer Biology and Genetics, Memorial Sloan-Kettering Cancer Center, New York, New York 10065, USA [2] Weill Cornell Graduate School of Medical Sciences, New York, New York 10065, USA [3].

ABSTRACT
The translational control of oncoprotein expression is implicated in many cancers. Here we report an eIF4A RNA helicase-dependent mechanism of translational control that contributes to oncogenesis and underlies the anticancer effects of silvestrol and related compounds. For example, eIF4A promotes T-cell acute lymphoblastic leukaemia development in vivo and is required for leukaemia maintenance. Accordingly, inhibition of eIF4A with silvestrol has powerful therapeutic effects against murine and human leukaemic cells in vitro and in vivo. We use transcriptome-scale ribosome footprinting to identify the hallmarks of eIF4A-dependent transcripts. These include 5' untranslated region (UTR) sequences such as the 12-nucleotide guanine quartet (CGG)4 motif that can form RNA G-quadruplex structures. Notably, among the most eIF4A-dependent and silvestrol-sensitive transcripts are a number of oncogenes, superenhancer-associated transcription factors, and epigenetic regulators. Hence, the 5' UTRs of select cancer genes harbour a targetable requirement for the eIF4A RNA helicase.

Show MeSH
Related in: MedlinePlus