Regulation of MYC Expression and Differential JQ1 Sensitivity in Cancer Cells

Fowler, Trent; Ghatak, Payel; Price, David H.; Conaway, Ronald C.; Conaway, Joan Weliky; Chiang, Cheng Ming; Bradner, James E.; Shilatifard, Ali; Roy, Ananda L.

doi:10.1371/journal.pone.0087003

Cited by 56 publications

(52 citation statements)

References 52 publications

(78 reference statements)

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“…S7B). These findings are consistent with a recent report showing that JQ1 decreases BRD4 occupancy on the c-MYC locus not only in the JQ1-sensitive cells – cells that show c-MYC mRNA repression following JQ1 treatment – but also in the JQ1-insensitive cells (46). JQ1 blocked BRD4 recruitment to the c-MYC locus even in cells that did not demonstrate any changes in c-MYC mRNA following JQ1 treatment (46).…”

Section: Discussionsupporting

confidence: 93%

BET Bromodomain Inhibitors Block Growth of Pancreatic Cancer Cells in Three-Dimensional Collagen

Sahai¹,

Kumar

Knab

et al. 2014

Molecular Cancer Therapeutics

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Pancreatic ductal adenocarcinoma (PDAC) is associated with pronounced fibrosis that contributes to chemoresistance, in part, through increased histone acetylation. Since bromodomain (BRD) and extra terminal domain (BET) proteins are ‘readers’ of histone acetylation marks, we targeted BET proteins in PDAC cells grown in three-dimensional collagen. We show that treatment with BET inhibitors decreases growth of PDAC cells (AsPC1, CD18 and Panc1) in collagen. Transfection with siRNA against BRD4, which is increased in human PDAC tumors, also decreases growth of PDAC cells. BET inhibitors additionally decrease growth in collagen of PDAC cells that have undergone epithelial-to-mesenchymal transition or have become resistant to chemotherapy. Although BET inhibitors and BRD4 siRNA repress c-MYC only in AsPC1 and CD18 cells, downregulating c-MYC decreases growth of all three PDAC cell lines in collagen. FOSL1, which is also targeted by BET inhibitors and BRD4 siRNA in AsPC1, CD18 and Panc1 cells, additionally regulates growth of all three PDAC cell lines in collagen. BET inhibitors and BRD4 siRNA repress HMGA2, an architectural protein that modulates chromatin state and also contributes to chemoresistance, in PDAC cells grown in collagen. Importantly, we show that there is a statistically significant correlation between BRD4 and HMGA2 in human PDAC tumors. Significantly, overexpression of HMGA2 partially mitigates the effect of BET inhibitors on growth and c-MYC and/or FOSL1 expression in collagen. Overall, these results demonstrate that BET inhibitors block growth of PDAC cells in collagen and that BET proteins may be potential targets for the treatment of pancreatic cancer.

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Section: Discussionsupporting

confidence: 93%

BET Bromodomain Inhibitors Block Growth of Pancreatic Cancer Cells in Three-Dimensional Collagen

Sahai¹,

Kumar

Knab

et al. 2014

Molecular Cancer Therapeutics

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“…The transcription of both HAS2 and IL7R have recently been reported to be potently down-regulated by BET BRD inhibition in tumor cell lines and are thought to play key roles in cell growth and survival (46,47). Consistent with previous observations that BRD inhibitors have differential effects on MYC, we also did not observe a reduction of MYC in HeLa cells (48); however, transcripts for cytokines IL-6 and IL-8, known to be increased in HeLa cells by EGF-mediated signaling (49), were suppressed by BRD inhibition. Our transcriptome profiling indicates that pharmacological inhibition of ERK5 kinase activity has no significant impact on gene transcription in two cell models, suggesting that phenotypes observed from genetic ablation of ERK5 result from kinase signaling-independent mechanisms.…”

Section: Characterization Of Inhibitors In Cancer Cell Proliferation supporting

confidence: 91%

ERK5 kinase activity is dispensable for cellular immune response and proliferation

Lin¹,

Amantea²,

Nomanbhoy³

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

104

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Unlike other members of the MAPK family, ERK5 contains a large C-terminal domain with transcriptional activation capability in addition to an N-terminal canonical kinase domain. Genetic deletion of ERK5 is embryonic lethal, and tissue-restricted deletions have profound effects on erythroid development, cardiac function, and neurogenesis. In addition, depletion of ERK5 is antiinflammatory and antitumorigenic. Small molecule inhibition of ERK5 has been shown to have promising activity in cell and animal models of inflammation and oncology. Here we report the synthesis and biological characterization of potent, selective ERK5 inhibitors. In contrast to both genetic depletion/deletion of ERK5 and inhibition with previously reported compounds, inhibition of the kinase with the most selective of the new inhibitors had no antiinflammatory or antiproliferative activity. The source of efficacy in previously reported ERK5 inhibitors is shown to be off-target activity on bromodomains, conserved protein modules involved in recognition of acetyl-lysine residues during transcriptional processes. It is likely that phenotypes reported from genetic deletion or depletion of ERK5 arise from removal of a noncatalytic function of ERK5. The newly reported inhibitors should be useful in determining which of the many reported phenotypes are due to kinase activity and delineate which can be pharmacologically targeted.) is a member of the mitogen-activated protein kinase (MAPK) family, which includes ERK1/2, JNK1/2/3, and p38α/β/δ/γ (1). However, unlike the other MAPK members, ERK5 contains a unique 400-amino-acid C-terminal domain in addition to the kinase domain. Through the MAPK signaling cascade, mitogenactivated protein kinase kinase 5 (MEK5) activates ERK5 by phosphorylating the TEY motif in the N-terminal activation loop (2). This event unlocks the N-and C-terminal halves, allowing ERK5 to auto-phosphorylate multiple sites in its C-terminal region, which can then regulate nuclear shuttling and gene transcription (3, 4). Noncanonical pathways (including cyclin-dependent kinases during mitosis and ERK1/2 during growth factor stimulation) also exist for phosphorylation of sites in the ERK5 tail (5-7). Although ERK5 has been demonstrated to directly phosphorylate transcription factors (8-10), the noncatalytic C-terminal tail of ERK5 can also interact with transcription factors and influence gene expression (4,11,12).ERK5 can be activated in response to a range of mitogenic stimuli [e.g., growth factors, G protein-coupled receptor (GPCR) agonists, cytokines] and cellular stresses (e.g., hypoxia, shear stress) (13). Like most kinases including MAPK members, ERK5 function is assumed to be driven by its kinase activity. ERK5 deletion is embryonic lethal in mice and a variety of tissue-or development-stage restricted KOs have shown clear phenotypes, suggesting that the catalytic function and/or an aspect of the nonkinase domain(s) have key roles in development and mature organ function (14-18). The availability of the first ERK5 inhibitor ...

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“…Importantly, inhibitors that target both bromodomains have a much stronger effect on gene regulation than a BD2-selective compound [43]. Dual bromodomain inhibitors strongly abrogate expression of c-Myc and of the downstream network, in line with their strong antiproliferative activity [2,44,45]. Even though the down-regulation of c-Myc transcript levels is only transient, the effects are much longer lasting at the protein level.…”

Section: Cell Proliferation Controlmentioning

confidence: 94%

Targeting BET Bromodomains for Cancer Treatment

et al. 2015

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The bromodomain and extraterminal (BET) subfamily of bromodomain-containing proteins has emerged in the last few years as an exciting, novel target group. BRD4, the best studied BET protein, is implicated in a number of hematological and solid tumors. This is linked to its role in modulating transcription elongation of essential genes involved in cell cycle and apoptosis such as c-Myc and BCL2. Potent BET inhibitors with promising antitumor efficacy in a number of preclinical cancer models have been identified in recent years. This led to clinical studies focusing mostly on the treatment of leukemia and lymphoma, and first encouraging signs of efficacy have already been reported. Here we discuss the biology of BRD4, its known interaction partners and implication in different tumor types. Further, we summarize the current knowledge on BET bromodomain inhibitors.

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Regulation of MYC Expression and Differential JQ1 Sensitivity in Cancer Cells

Cited by 56 publications

References 52 publications

BET Bromodomain Inhibitors Block Growth of Pancreatic Cancer Cells in Three-Dimensional Collagen

BET Bromodomain Inhibitors Block Growth of Pancreatic Cancer Cells in Three-Dimensional Collagen

ERK5 kinase activity is dispensable for cellular immune response and proliferation

Targeting BET Bromodomains for Cancer Treatment

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