Limits...
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.

Show MeSH

Related in: MedlinePlus

Many oncogenes and transcription factors require eIF4A for translationa) TE down genes ranked by translational efficiency (red, up to p = 0.01, see Fig. 3b); b) rDiff genes ranked by significance (up to p = 0.001, see Fig. 3c); c) Genes associated with “super-enhancers” in T-ALL cells are enriched among TE down and rDiff gene sets; d) Immunoblots of lysates from human T-ALL lines treated with Silvestrol (25 nM, 24h) and probed as indicated; e) Time course analysis of protein expression in KOPT-K1 cells treated with CR (25 nM) for the indicated number of hours; f) Immunoblot on CR or vehicle treated KOPT-K1 xenografts, probed as indicated; g) Competition experiment (as in Figure 1c/d) showing the percentage of each starting GFP positive population of murine T-ALL cells partially transduced with the indicated constructs and treated with Silvestrol (*indicates p <0.05); h) Diagram: An eIF4A-dependent mechanism of translational control.
© Copyright Policy
Related In: Results  -  Collection

License
getmorefigures.php?uid=PMC4492470&req=5

Figure 5: Many oncogenes and transcription factors require eIF4A for translationa) TE down genes ranked by translational efficiency (red, up to p = 0.01, see Fig. 3b); b) rDiff genes ranked by significance (up to p = 0.001, see Fig. 3c); c) Genes associated with “super-enhancers” in T-ALL cells are enriched among TE down and rDiff gene sets; d) Immunoblots of lysates from human T-ALL lines treated with Silvestrol (25 nM, 24h) and probed as indicated; e) Time course analysis of protein expression in KOPT-K1 cells treated with CR (25 nM) for the indicated number of hours; f) Immunoblot on CR or vehicle treated KOPT-K1 xenografts, probed as indicated; g) Competition experiment (as in Figure 1c/d) showing the percentage of each starting GFP positive population of murine T-ALL cells partially transduced with the indicated constructs and treated with Silvestrol (*indicates p <0.05); h) Diagram: An eIF4A-dependent mechanism of translational control.

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)

Many oncogenes and transcription factors require eIF4A for translationa) TE down genes ranked by translational efficiency (red, up to p = 0.01, see Fig. 3b); b) rDiff genes ranked by significance (up to p = 0.001, see Fig. 3c); c) Genes associated with “super-enhancers” in T-ALL cells are enriched among TE down and rDiff gene sets; d) Immunoblots of lysates from human T-ALL lines treated with Silvestrol (25 nM, 24h) and probed as indicated; e) Time course analysis of protein expression in KOPT-K1 cells treated with CR (25 nM) for the indicated number of hours; f) Immunoblot on CR or vehicle treated KOPT-K1 xenografts, probed as indicated; g) Competition experiment (as in Figure 1c/d) showing the percentage of each starting GFP positive population of murine T-ALL cells partially transduced with the indicated constructs and treated with Silvestrol (*indicates p <0.05); h) Diagram: An eIF4A-dependent mechanism of translational control.
© Copyright Policy
Related In: Results  -  Collection

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

Figure 5: Many oncogenes and transcription factors require eIF4A for translationa) TE down genes ranked by translational efficiency (red, up to p = 0.01, see Fig. 3b); b) rDiff genes ranked by significance (up to p = 0.001, see Fig. 3c); c) Genes associated with “super-enhancers” in T-ALL cells are enriched among TE down and rDiff gene sets; d) Immunoblots of lysates from human T-ALL lines treated with Silvestrol (25 nM, 24h) and probed as indicated; e) Time course analysis of protein expression in KOPT-K1 cells treated with CR (25 nM) for the indicated number of hours; f) Immunoblot on CR or vehicle treated KOPT-K1 xenografts, probed as indicated; g) Competition experiment (as in Figure 1c/d) showing the percentage of each starting GFP positive population of murine T-ALL cells partially transduced with the indicated constructs and treated with Silvestrol (*indicates p <0.05); h) Diagram: An eIF4A-dependent mechanism of translational control.
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