The role of supercoiling in transcriptional control of MYC and its importance in molecular therapeutics

Brooks, Tracy A.; Hurley, Laurence H.

doi:10.1038/nrc2733

Cited by 264 publications

(279 citation statements)

References 127 publications

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“…With MYC's role in so many hallmarks of cancer, and growth related events, it is easy to understand why its deregulation is found so frequently as either a causative oncogenic event, or distinctly tied to prognosis and therapy. It is also something to which cancer cells often seem addicted, providing a window of opportunity for new anticancer therapies (15). Specific targeting of protein function has yet to be a successful avenue of drug development.…”

Section: Discussionmentioning

confidence: 99%

“…Modulation of Protein Binding to the MYC NHE III 1 with GQC-05-Many extensive studies have been performed to describe the binding of transcription factors to the MYC core promoter, as well as the resolution and stabilization of the MYC promoter G4 (15,33,34,49). Using GQC-05, we monitored the modulation of the known transcriptional factors and regulatory proteins bound to the NHE III 1 region of MYC and showed that within six to twelve hours of small molecule administration, most of these proteins were significantly decreased in both BL cell lines (Figs.…”

Section: Discussionmentioning

confidence: 99%

“…Deregulated MYC can lead to transformation (15), often as an early step in the process of multistage cancer development, and one on which all other mutations are based (16,17). Cancer cells appear to be addicted to a deregulated MYC (18), which can be the "Achilles heel", offering the potential for a therapeutic window (19,20).…”

mentioning

confidence: 99%

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Demonstration that Drug-targeted Down-regulation of MYC in Non-Hodgkins Lymphoma Is Directly Mediated through the Promoter G-quadruplex

Brown

Danford

Gokhale

et al. 2011

Journal of Biological Chemistry

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157

221

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Most transcription of the MYC proto-oncogene initiates in the near upstream promoter, within which lies the nuclease hypersensitive element (NHE) III 1 region containing the CT-element. This dynamic stretch of DNA can form at least three different topologies: single-stranded DNA, double-stranded DNA, or higher order secondary structures that silence transcription. In the current report, we identify the ellipticine analog GQC-05 (NSC338258) as a high affinity, potent, and selective stabilizer of the MYC G-quadruplex (G4). In cells, GQC-05 induced cytotoxicity with corresponding decreased MYC mRNA and altered protein binding to the NHE III 1 region, in agreement with a G4 stabilizing compound. We further describe a unique feature of the Burkitt's lymphoma cell line CA46 that allowed us to clearly demonstrate the mechanism and location of action of GQC-05 within this region of DNA and through the G4. Most importantly, these data present, as far as we are aware, the most direct evidence of intracellular G4-mediated control of a particular promoter.The MYC proto-oncogene is a key component of normal cell growth and differentiation, with roles in a multitude of cellular processes. Normally, this gene is subject to tight transcriptional regulation; however, aberrant MYC expression is a common feature in an estimated 80% of all human malignancies (1-3); it is estimated that one-seventh of cancer deaths in the United States are associated with alterations in the MYC gene or its expression (4). Deregulation can arise through a variety of mechanisms (5-13), but most often MYC is activated through alterations in cell signaling that lead to increased transcription (14).Deregulated MYC can lead to transformation (15), often as an early step in the process of multistage cancer development, and one on which all other mutations are based (16,17). Cancer cells appear to be addicted to a deregulated MYC (18), which can be the "Achilles heel", offering the potential for a therapeutic window (19,20). The ability to selectively and potently down-regulate MYC would have considerable potential for both efficacy and safety in a variety of tumor types.There are several upstream elements within the MYC promoter that can potentially undergo strand separation to form either single-stranded or other non-B-DNA structures (21), which play a critical role in transcriptional control of MYC: the distant Far Upstream Element acts as a cruise control element, Z-DNA found both in the far upstream and the promoter regions, and a GC-rich region within the proximal promoter that acts as an on/off switch (22-28). This near upstream core promoter region, which is responsible for the initiation of 80 -90% of MYC transcription (29), contains the GC-rich nuclease hypersensitive element (NHE) 2 III 1 to which doublestranded (Sp1) and single-stranded (CNBP and hnRNP k) transcriptional factors bind. Within the MYC gene's NHE III 1 , a 31-base pair element consisting of five repeats of the sequence (C/T)C(C/T)TCCCCA serves as the "on/off switch" for MYC trans...

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Section: Discussionmentioning

confidence: 99%

Section: Discussionmentioning

confidence: 99%

See 1 more Smart Citation

Demonstration that Drug-targeted Down-regulation of MYC in Non-Hodgkins Lymphoma Is Directly Mediated through the Promoter G-quadruplex

Brown

Danford

Gokhale

et al. 2011

Journal of Biological Chemistry

Self Cite

157

221

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“…64 Accordingly, in silico analyses showed a high enrichment of these sequences at regulatory regions of the genome and, notably, at the promoters of a wide range of oncogenes. [85][86][87][88] In addition, several conformation-sensitive proteins with regulatory function bind and stabilize non-B DNAs, suggesting an important role of these structures in transcriptional output. 64 Another way to make genetic processes more tolerant to the constrained DNA topology is weakening the DNA through introducing double strand breaks or nicks.…”

Section: Dna Topology and Genome Architecturementioning

confidence: 99%

DNA topology and transcription

Kouzine¹,

Levens²,

Baranello³

2014

Nucleus

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Chromatin is a complex assembly that compacts DNA inside the nucleus while providing the necessary level of accessibility to regulatory factors conscripted by cellular signaling systems. In this superstructure, DNA is the subject of mechanical forces applied by variety of molecular motors. Rather than being a rigid stick, DNA possesses dynamic structural variability that could be harnessed during critical steps of genome functioning. The strong relationship between DNA structure and key genomic processes necessitates the study of physical constrains acting on the double helix. Here we provide insight into the source, dynamics, and biology of DNA topological domains in the eukaryotic cells and summarize their possible involvement in gene transcription. We emphasize recent studies that might inspire and impact future experiments on the involvement of DNA topology in cellular functions.

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“…It remains largely unexplored as to how this pathway is regulated under normal or stressed conditions. Among numerous notable transcriptional factors, cMyc is well known to regulate up to 10%-15% human genes involved in cell cycle, development, apoptosis and metabolism [32][33][34]. Interestingly, it has been suggested recently that cMyc is posed to amplify all the extant expressed genes [35,36].…”

Section: Introductionmentioning

confidence: 99%

cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

et al. 2015

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Cancer cells are known to undergo metabolic reprogramming to sustain survival and rapid proliferation, however, it remains to be fully elucidated how oncogenic lesions coordinate the metabolic switch under various stressed conditions. Here we show that deprivation of glucose or glutamine, two major nutrition sources for cancer cells, dramatically activated serine biosynthesis pathway (SSP) that was accompanied by elevated cMyc expression. We further identified that cMyc stimulated SSP activation by transcriptionally upregulating expression of multiple SSP enzymes. Moreover, we demonstrated that SSP activation facilitated by cMyc led to elevated glutathione (GSH) production, cell cycle progression and nucleic acid synthesis, which are essential for cell survival and proliferation especially under nutrient-deprived conditions. We further uncovered that phosphoserine phosphatase (PSPH), the final rate-limiting enzyme of the SSP pathway, is critical for cMyc-driven cancer progression both in vitro and in vivo, and importantly, aberrant expression of PSPH is highly correlated with mortality in hepatocellular carcinoma (HCC) patients, suggesting a potential causal relation between this cMyc-regulated enzyme, or SSP activation in general, and cancer development. Taken together, our results reveal that aberrant expression of cMyc leads to the enhanced SSP activation, an essential part of metabolic switch, to facilitate cancer progression under nutrient-deprived conditions.

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The role of supercoiling in transcriptional control of MYC and its importance in molecular therapeutics

Cited by 264 publications

References 127 publications

Demonstration that Drug-targeted Down-regulation of MYC in Non-Hodgkins Lymphoma Is Directly Mediated through the Promoter G-quadruplex

Demonstration that Drug-targeted Down-regulation of MYC in Non-Hodgkins Lymphoma Is Directly Mediated through the Promoter G-quadruplex

DNA topology and transcription

cMyc-mediated activation of serine biosynthesis pathway is critical for cancer progression under nutrient deprivation conditions

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