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Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism.

Lu H, Xue Y, Xue Y, Yu GK, Arias C, Lin J, Fong S, Faure M, Weisburd B, Ji X, Mercier A, Sutton J, Luo K, Gao Z, Zhou Q - Elife (2015)

Bottom Line: Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing.While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment.Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9's activity and resistance to inhibition.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.

ABSTRACT
CDK9 is the kinase subunit of positive transcription elongation factor b (P-TEFb) that enables RNA polymerase (Pol) II's transition from promoter-proximal pausing to productive elongation. Although considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing. While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment. Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9's activity and resistance to inhibition. Because the i-CDK9-induced MYC expression and binding to P-TEFb compensate for P-TEFb's loss of activity, only simultaneously inhibiting CDK9 and MYC/BRD4 can efficiently induce growth arrest and apoptosis of cancer cells, suggesting the potential of a combinatorial treatment strategy.

No MeSH data available.


Related in: MedlinePlus

JQ1 decreases associations of both BRD4 and CDK9 with the MYC locus.DOI:http://dx.doi.org/10.7554/eLife.06535.012
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fig4s2: JQ1 decreases associations of both BRD4 and CDK9 with the MYC locus.DOI:http://dx.doi.org/10.7554/eLife.06535.012

Mentions: To determine if the binding of BRD4 to acetylated chromatin is required for i-CDK9 to induce MYC expression, we tested whether the BET bromodomain inhibitor JQ1 could block the induction. JQ1 is known to competitively bind to the acetyl-lysine recognition pocket within BRD4's bromodomains, leading to the dissociation of the BRD4-P-TEFb complex from acetylated chromatin (Zuber et al., 2011; Li et al., 2013). Consistent with the results obtained in other cell types (Mertz et al., 2011; Zuber et al., 2011), JQ1 decreased the associations of both BRD4 and CDK9 with the MYC locus in HeLa cells (Figure 4—figure supplement 2). More importantly, JQ1 also completely abolished the MYC induction by i-CDK9 in HeLa (Figure 4C) as well as the lung cancer cell line H1792 and the melanoma cell line A2058 (Figure 4—figure supplement 3), whereas the control enantiomer was ineffective in this regard. These observations, in conjunction with the shBRD4 result above, confirm that the interaction between BRD4 and acetylated chromatin is required for i-CDK9 to induce MYC expression in diverse cell types.


Compensatory induction of MYC expression by sustained CDK9 inhibition via a BRD4-dependent mechanism.

Lu H, Xue Y, Xue Y, Yu GK, Arias C, Lin J, Fong S, Faure M, Weisburd B, Ji X, Mercier A, Sutton J, Luo K, Gao Z, Zhou Q - Elife (2015)

JQ1 decreases associations of both BRD4 and CDK9 with the MYC locus.DOI:http://dx.doi.org/10.7554/eLife.06535.012
© Copyright Policy
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4490784&req=5

fig4s2: JQ1 decreases associations of both BRD4 and CDK9 with the MYC locus.DOI:http://dx.doi.org/10.7554/eLife.06535.012
Mentions: To determine if the binding of BRD4 to acetylated chromatin is required for i-CDK9 to induce MYC expression, we tested whether the BET bromodomain inhibitor JQ1 could block the induction. JQ1 is known to competitively bind to the acetyl-lysine recognition pocket within BRD4's bromodomains, leading to the dissociation of the BRD4-P-TEFb complex from acetylated chromatin (Zuber et al., 2011; Li et al., 2013). Consistent with the results obtained in other cell types (Mertz et al., 2011; Zuber et al., 2011), JQ1 decreased the associations of both BRD4 and CDK9 with the MYC locus in HeLa cells (Figure 4—figure supplement 2). More importantly, JQ1 also completely abolished the MYC induction by i-CDK9 in HeLa (Figure 4C) as well as the lung cancer cell line H1792 and the melanoma cell line A2058 (Figure 4—figure supplement 3), whereas the control enantiomer was ineffective in this regard. These observations, in conjunction with the shBRD4 result above, confirm that the interaction between BRD4 and acetylated chromatin is required for i-CDK9 to induce MYC expression in diverse cell types.

Bottom Line: Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing.While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment.Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9's activity and resistance to inhibition.

View Article: PubMed Central - PubMed

Affiliation: Department of Molecular and Cell Biology, University of California, Berkeley, Berkeley, United States.

ABSTRACT
CDK9 is the kinase subunit of positive transcription elongation factor b (P-TEFb) that enables RNA polymerase (Pol) II's transition from promoter-proximal pausing to productive elongation. Although considerable interest exists in CDK9 as a therapeutic target, little progress has been made due to lack of highly selective inhibitors. Here, we describe the development of i-CDK9 as such an inhibitor that potently suppresses CDK9 phosphorylation of substrates and causes genome-wide Pol II pausing. While most genes experience reduced expression, MYC and other primary response genes increase expression upon sustained i-CDK9 treatment. Essential for this increase, the bromodomain protein BRD4 captures P-TEFb from 7SK snRNP to deliver to target genes and also enhances CDK9's activity and resistance to inhibition. Because the i-CDK9-induced MYC expression and binding to P-TEFb compensate for P-TEFb's loss of activity, only simultaneously inhibiting CDK9 and MYC/BRD4 can efficiently induce growth arrest and apoptosis of cancer cells, suggesting the potential of a combinatorial treatment strategy.

No MeSH data available.


Related in: MedlinePlus