YB-1, the E2F Pathway, and Regulation of Tumor Cell Growth

Lasham, Annette; Samuel, Weini; Cao, Helen; Patel, Rachna; Mehta, Reena; Stern, Josh Lewis; Reid, Glen; Woolley, Adele G.; Miller, Lance D.; Black, Michael A.; Shelling, Andrew N.; Print, Cristin G.; Braithwaite, Antony W.

doi:10.1093/jnci/djr512

Cited by 108 publications

(154 citation statements)

References 73 publications

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“…Focusing on the global picture, transcription profiling analysis after functional inactivation is available both for YB-1 123 and NF-Y. 124 In YB-1-regulated genes, an abundance of E2F sites was reported: we re-examined these data with bioinformatic tools and indeed confirm this point, but neither the Y/CCAAT logo nor related variants are overrepresented (Figure 3).…”

Section: Nf-y Is the Sequence-specific Ccaat Factormentioning

confidence: 68%

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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Section: Nf-y Is the Sequence-specific Ccaat Factormentioning

confidence: 68%

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

Dolfini

Mantovani

2013

Cell Death Differ

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“…RSK2 mRNA levels were assessed in RMA-normalized Affymetrix HG-U133A or HG-U133PLUS2 microarray data from 771 clinically annotated breast tumors drawn from five breast cancer cohorts as previously described [33]. Using the only probe set for RSK2 (RPS6KA3-203843_at), expression levels were plotted against histological grade and subtype for all 771 patients, followed by one-way analysis of variance and Tukey's Honestly Significant Difference test to determine the statistical significance, using the R statistical environment.…”

Section: Rsk2 Survival and Subtype Analysesmentioning

confidence: 99%

Targeting p90 Ribosomal S6 Kinase Eliminates Tumor-Initiating Cells by Inactivating Y-Box Binding Protein-1 in Triple-Negative Breast Cancers

Stratford

Reipas

et al. 2012

Stem Cells

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Y-box binding protein-1 (YB-1) is the first reported oncogenic transcription factor to induce the tumor-initiating cell (TIC) surface marker CD44 in triple-negative breast cancer (TNBC) cells. In order for CD44 to be induced, YB-1 must be phosphorylated at S102 by p90 ribosomal S6 kinase (RSK). We therefore questioned whether RSK might be a tractable molecular target to eliminate TICs. In support of this idea, injection of MDA-MB-231 cells expressing Flag-YB-1 into mice increased tumor growth as well as enhanced CD44 expression. Despite enrichment for TICs, these cells were sensitive to RSK inhibition when treated ex vivo with BI-D1870. Targeting RSK2 with small interfering RNA (siRNA) or small molecule RSK kinase inhibitors (SL0101 and BI-D1870) blocked TNBC monolayer cell growth by $100%. In a diverse panel of breast tumor cell line models RSK2 siRNA predominantly targeted models of TNBC. RSK2 inhibition decreased CD44 promoter activity, CD44 mRNA, protein expression, and mammosphere formation. CD44 1 cells had higher P-RSK S221/227 , P-YB-1 S102 , and mitotic activity relative to CD44 2 cells. Importantly, RSK2 inhibition specifically suppressed the growth of TICs and triggered cell death. Moreover, silencing RSK2 delayed tumor initiation in mice. In patients, RSK2 mRNA was associated with poor disease-free survival in a cohort of 244 women with breast cancer that had not received adjuvant treatment, and its expression was highest in the basal-like breast cancer subtype. Taking this further, we report that P-RSK S221/227 is present in primary TNBCs and correlates with P-YB-1 S102 as well as CD44. In conclusion, RSK2 inhibition provides a novel therapeutic avenue for TNBC and holds the promise of eliminating TICs.

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“…By binding to their target mRNAs, RBPs could in turn contribute to the tuning of the p53-induced responses both at the transcriptional and translational levels. We chose SRSF1 and YBX1 to explore these potential regulatory modules by an siRNA approach, as they both control cell proliferation, cell-cycle progression and apoptosis 36,37 (Figure 4h). We confirmed data indicating that SRSF1 reduction leads to a lower stabilization of p53 protein and to lower induction of p21.…”

Section: Resultsmentioning

confidence: 99%