Revealing Global Regulatory Perturbations across Human Cancers

Goodarzi, Hani; Elemento, Olivier; Tavazoie, Saeed

doi:10.1016/j.molcel.2009.11.016

Cited by 203 publications

(278 citation statements)

References 50 publications

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“…4D, right panel). And lastly, we also analyzed the RNAseq data with the iPAGE gene expression analysis tool (42). This analysis identified the unfolded protein binding function as being significantly up-regulated in three out of four primary AML specimens treated with PDT (supplemental Fig.…”

Section: Pdt Regimen Does Not Affect Nf-b Signaling But Induces Stronmentioning

confidence: 99%

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Pei¹,

Minhajuddin²,

D’Alessandro

et al. 2016

Journal of Biological Chemistry

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Although multidrug approaches to cancer therapy are common, few strategies are based on rigorous scientific principles. Rather, drug combinations are largely dictated by empirical or clinical parameters. In the present study we developed a strategy for rational design of a regimen that selectively targets human acute myelogenous leukemia (AML) stem cells. As a starting point, we used parthenolide, an agent shown to target critical mechanisms of redox balance in primary AML cells. Next, using proteomic, genomic, and metabolomic methods, we determined that treatment with parthenolide leads to induction of compensatory mechanisms that include up-regulated NADPH production via the pentose phosphate pathway as well as activation of the Nrf2-mediated oxidative stress response pathway. Using this knowledge we identified 2-deoxyglucose and temsirolimus as agents that can be added to a parthenolide regimen as a means to inhibit such compensatory events and thereby further enhance eradication of AML cells. We demonstrate that the parthenolide, 2-deoxyglucose, temsirolimus (termed PDT) regimen is a potent means of targeting AML stem cells but has little to no effect on normal stem cells. Taken together our findings illustrate a comprehensive approach to designing combination anticancer drug regimens.Numerous studies have documented the biological complexity of human tumor cell populations in which genetic, epigenetic, biochemical, and metabolic properties can often be quite heterogeneous (1, 2). As a result, complicated multidrug regimens are often employed to target various components of tumor biology and/or acquired drug resistance (3, 4). However, the rationale behind the design of multidrug regimens is usually inconsistent and often driven by pragmatism more than scientific rigor. Thus, establishing more effective means by which to identify optimal drug regimens is an important priority, particularly with the recent emergence of a broad range of targeted agents.

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Section: Pdt Regimen Does Not Affect Nf-b Signaling But Induces Stronmentioning

confidence: 99%

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Pei¹,

Minhajuddin²,

D’Alessandro

et al. 2016

Journal of Biological Chemistry

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“…The CCAAT-box, regarded as a binding site for NF-Y, was recently found to be a common cis-regulatory motif in the promoters of genes up-regulated in pluripotent stem cells (30), and it was also highly enriched in regulatory regions of genes overexpressed in tumors (31). Subunit NF-YA has two different isoforms, NF-YAL (long) and NF-YAS (short), resulting from alternative splicing (24).…”

Section: Discussionmentioning

confidence: 99%

Transcriptional Activation of Human CDCA8 Gene Regulated by Transcription Factor NF-Y in Embryonic Stem Cells and Cancer Cells

Dai

Miao

et al. 2015

Journal of Biological Chemistry

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Background:The regulation of CDCA8 gene expression remains unclear. Results: CDCA8 promoter is activated in hESCs and cancer cells, in which NF-Y is a positive-regulator by binding to the CCAAT-box. Conclusion: CDCA8 is transcriptionally activated in hESCs and cancer cells and is positively regulated by NF-Y. Significance: Characterization of CDCA8 regulation provides a better understanding of its biological functions.

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“…More tellingly, de novo motif discovery methods that allow unbiased identification of sequence logos showed that promoters of genes, specifically overexpressed in tumors, are significantly enriched in Y/CCAAT elements. [32][33][34] This indicates that Y/CCAAT is of importance in the overexpression of cancer genes in tumors. Therefore, the TFs recognizing this element are likely relevant for the process of cellular transformation.…”

Section: Y and Ccaat: Two Names One Entitymentioning

confidence: 98%

Targeting the Y/CCAAT box in cancer: YB-1 (YBX1) or NF-Y?

Dolfini

Mantovani

2013

Cell Death Differ

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The Y box is an important sequence motif found in promoters and enhancers containing a CCAAT box -one of the few elements enriched in promoters of large sets of genes overexpressed in cancer. The search for the transcription factor(s) acting on it led to the biochemical purification of the nuclear factor Y (NF-Y) heterotrimer, and to the cloning -through the screening of expression libraries -of Y box-binding protein 1 (YB-1), an oncogene, overexpressed in aggressive tumors and associated with drug resistance. These two factors have been associated with Y/CCAAT-dependent activation of numerous growth-related genes, notably multidrug resistance protein 1. We review two decades of data indicating that NF-Y ultimately acts on Y/CCAAT in cancer cells, a notion recently confirmed by genome-wide data. Other features of YB-1, such as post-transcriptional control of mRNA biology, render it important in cancer biology.

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Revealing Global Regulatory Perturbations across Human Cancers

Cited by 203 publications

References 50 publications

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Rational Design of a Parthenolide-based Drug Regimen That Selectively Eradicates Acute Myelogenous Leukemia Stem Cells

Transcriptional Activation of Human CDCA8 Gene Regulated by Transcription Factor NF-Y in Embryonic Stem Cells and Cancer Cells

Targeting the Y/CCAAT box in cancer: YB-1 (YBX1) or NF-Y?

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