scholarly journals Role of the Transcription Factor Yin Yang 1 and Its Selectively Identified Target Survivin in High-Grade B-Cells Non-Hodgkin Lymphomas: Potential Diagnostic and Therapeutic Targets

2020 ◽  
Vol 21 (17) ◽  
pp. 6446
Author(s):  
Silvia Vivarelli ◽  
Luca Falzone ◽  
Giovanni Ligresti ◽  
Saverio Candido ◽  
Adriana Garozzo ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Therapeutic Targets ◽  
Gene Expression Omnibus ◽  
Drug Induced ◽  
Apoptotic Pathway ◽  
Yin Yang 1 ◽  
Yin Yang ◽  
Induced Apoptosis ◽  
Transcriptional Target

B-cell non-Hodgkin lymphomas (B-NHLs) are often characterized by the development of resistance to chemotherapeutic drugs and/or relapse. During drug-induced apoptosis, Yin Yang 1 (YY1) transcription factor might modulate the expression of apoptotic regulators genes. The present study was aimed to: (1) examine the potential oncogenic role of YY1 in reversing drug resistance in B-NHLs; and (2) identify YY1 transcriptional target(s) that regulate the apoptotic pathway in B-NHLs. Predictive analyses coupled with database-deposited data suggested that YY1 binds the promoter of the BIRC5/survivin anti-apoptotic gene. Gene Expression Omnibus (GEO) analyses of several B-NHL repositories revealed a conserved positive correlation between YY1 and survivin, both highly expressed, especially in aggressive B-NHLs. Further validation experiments performed in Raji Burkitt’s lymphomas cells, demonstrated that YY1 silencing was associated with survivin downregulation and sensitized the cells to apoptosis. Overall, our results revealed that: (1) YY1 and survivin are positively correlated and overexpressed in B-NHLs, especially in BLs; (2) YY1 strongly binds to the survivin promoter, hence survivin may be suggested as YY1 transcriptional target; (3) YY1 silencing sensitizes Raji cells to drug-induced apoptosis via downregulation of survivin; (4) both YY1 and survivin are potential diagnostic markers and therapeutic targets for the treatment of resistant/relapsed B-NHLs.

Rituximab-Mediated Inhibition of the Transcription Repressor Yin-Yang 1 (YY1) in NHL B Cell Lines: Upregulation of Fas Expression and Sensitization to Fas-Induced Apoptosis.

Blood ◽  
2004 ◽  
Vol 104 (11) ◽  
pp. 287-287
Author(s):  
Mario I. Vega ◽  
Sara Huerta-Yepez ◽  
Ali R. Jazirehi ◽  
Hermes Garban ◽  
Benjamin Bonavida
Keyword(s):  
B Cell ◽  
Cell Lines ◽  
Intracellular Signaling ◽  
Drug Induced ◽  
Apoptotic Pathway ◽  
Specific Chemical ◽  
Active Inhibitor ◽  
Yin Yang 1 ◽  
Yin Yang ◽  
Induced Apoptosis

Abstract We have reported that rituximab triggers and inhibits anti-apoptotic gene products in NHL B-cell lines resulting in sensitization to drug-induced apoptosis (Alas et al., Clin. Cancer Res.8:836, 2001; Jazirehi et al., Mol. Cancer Therapy2:1183, 2003; Vega et al., Oncogene23:3530, 2004 ). This study investigated whether rituximab also modifies intracellular signaling pathways resulting in the sensitization of NHL cells to Fas-induced apoptosis. Treatment of the NHL cell lines (2F7, Ramos, and Raji) with rituximab (20 μg/ml) sensitized the cells to CH-11 (FasL agonist mAb) -induced apoptosis and synergy was achieved. Fas expression was up-regulated by rituximab as early as 6 h post treatment as determined by flow cytometry, RT-PCR, and Western. Rituximab inhibited both the expression and activity of the transcription repressor Yin-Yang 1 (YY1) that negatively regulates Fas transcription. Inhibition of YY1 resulted in upregulation of Fas expression and sensitization of the tumor cells to CH-11-induced apoptosis. Downregulation of YY1 expression was the result of rituximab-induced inhibition of both the p38MAPK signaling pathway and constitutive NF- κB activity. The dual roles of NF-κB and YY1 in the regulation of Fas expression were corroborated by the use of a dominant-active inhibitor of NF- κB (Ramos IκB-ER mutant) and YY1 siRNA, respectively. The role of rituximab-mediated inhibition of the p38MAPK/NF- κB/YY1 pathways, which result in both Fas upregulation and sensitization to CH11-induced apoptosis, was corroborated by the use of specific chemical inhibitors directed at various targets of these pathways. Rituximab-mediated sensitization to CH-11-induced apoptosis was executed through the Type II mitochondrial apoptotic pathway. Altogether, these findings provide a novel mechanism of rituximab-mediated signaling by inhibiting the p38MAPK/NF- κB/YY1 pathways and resulting in the sensitization of B NHL to Fas-induced apoptosis. These findings may have significant clinical implications and suggest an additional mechanism of rituximab-mediated effect in vivo in addition to CDC and ADCC.

The Pivotal Role of Yin Yang 1 (YY1) Inhibition (and downstream Bcl-2/Bclxl) by Galiximab (anti-CD80 mAb) In the Reversal of Resistance of B-NHL Cells to Chemotherapy

Blood ◽  
2010 ◽  
Vol 116 (21) ◽  
pp. 2887-2887
Author(s):  
Melisa Martinez-Paniagua ◽  
Mario I. Vega ◽  
Sara Huerta-Yepez ◽  
Hari Hariharan ◽  
Haiming Chen ◽  
...  
Keyword(s):  
Tumor Cell ◽  
Conflicts Of Interest ◽  
Gene Products ◽  
Drug Induced ◽  
Raji Cells ◽  
Apoptotic Gene ◽  
Yin Yang 1 ◽  
Yin Yang ◽  
Induced Apoptosis

Abstract Abstract 2887 Galiximab (anti-CD80 mAb) is a primatized mAb (human IgG1 constant region and Cynomogous macaque variable region) that binds CD80 on lymphoma cells. It has been shown in vitro that Galiximab inhibits tumor cell proliferation and mediates ADCC. Galiximab is currently in clinical trials for a variety of cancers. Our preliminary findings demonstrated that Galiximab treatment of B-NHL cell lines, like Raji, triggers the cells and inhibits the constitutively activated NF-κB pathway. We hypothesized that Galiximab-induced inhibition of NF-κB may result in the inhibition downstream of several anti-apoptotic gene products and sensitizes cells to drug-induced apoptosis. Raji cells were treated with Galiximab (20-100 μg/ml) for 18h and followed by treatment with the chemotherapeutic drug CDDP (5-10 μg/ml) for 24h and apoptosis was determined by flow for activation of caspase 3. The findings demonstrated that the cells treated with Galiximab were sensitized to CDDP-induced apoptosis. Analysis of the apoptotic pathway following treatment with Galiximab revealed the inhibition of anti-apoptotic gene products such as Bcl-2 and Bclxl. We have also found that Galiximab, like rituximab, inhibits the Fas and DR5 transcription repressor Yin Yang 1 (YY1) and the direct inhibition of YY1 resulted in tumor cell sensitization to both Fas-L and TRAIL. We examined whether inhibition of YY1 by Galiximab was also involved in the sensitization to CDDP apoptosis. Raji cells were treated with YY1 siRNA and, unlike control siRNA or non-treated siRNA cells, the tumor cells were sensitized to CDDP apoptosis. The inhibition of YY1 by siRNA correlated with the inhibition of Bcl-2 and Bclxl. The direct role of Bcl-2 and Bclxl in the regulation of resistance was corroborated by treatment of cells with the Bcl-2 family inhibitor, 2MMA3, and such cells mimicked Galiximab and were sensitive to CDDP-induced apoptosis. The mechanism by which treatment with YY1 siRNA resulted in the inhibition of Bcl-2 and Bclxl and the reversal of resistance is not clear. We suggest that YY1 inhibition, following Galiximab-induced inhibition of NF-κB, will result in the inhibition of Snail transcription (Palmer, MB et al., Mol cancer Res 7:221, 2009). Inhibition of the RKIP (Raf kinase inhibitor protein) repressor Snail will result in the induction of RKIP (Wu, K and Bonavida, B Crit Rev immu 29:241, 2009) and, in turn, RKIP will inhibit NF-κB and resulting downstream in the inhibition of Bcl-2 and Bclxl. In addition, it has been reported that YY1 negatively regulates p53 (Sui, G et al., Cell 117:889, 2004) and YY1 inhibition by Galiximab will upregulate p53 and which will result in the inhibition of Bcl-2 and Bclxl (see scheme below). The present findings demonstrate that Galiximab sensitizes drug-resistant B-NHL cells to drug-induced apoptosis via modulation of the NF-κB/YY1/Snail/RKIP/p53 loop. Current studies are validating the present findings with freshly-derived B-NHL cells and also examining the molecular mechanism by which YY1 regulates Bcl-2/Bclxl expression and the reversal of resistance. Disclosures: No relevant conflicts of interest to declare.

Yin Yang 1 (YY1) Regulates The Transcription Of The Gene Krüppel-Like Factor 4 (KLF4) In Pediatric Burkitt Lymphoma: Clinical Implications

Blood ◽  
2013 ◽  
Vol 122 (21) ◽  
pp. 3004-3004
Author(s):  
Mario I Vega ◽  
Alberto Valencia-Hipolito ◽  
Miriam Hernandez-Atenogenes ◽  
Gabriel G Vega ◽  
Hector Mayani ◽  
...  
Keyword(s):  
Transcription Factor ◽  
B Cells ◽  
Binding Site ◽  
Conflicts Of Interest ◽  
Supporting Evidence ◽  
Apoptotic Pathway ◽  
Bioinformatics Analyses ◽  
Yin Yang 1 ◽  
Tumor Tissues ◽  
Yin Yang

Abstract Krüppel-like factor 4 (KLF4) is a member of the KLF zinc-finger containing transcription factor family. Supporting evidence has established that KLF4 is either an oncogene or a tumor suppressor. Reported studies have indicated the involvement of KLF4 in the regulation of apoptosis, proliferation, and differentiation of B cells and B-cell malignancies. In contrast to adult lymphomas and solid tumors, recently, we have shown in a TMA the overexpression of KLF4 in pediatric NHL tumor tissues. The KLF4 overexpresion predicted unresponsiveness to CHOP treatment. In addition, we have also reported that the transcription factor Yin Yang 1 (YY1) is overexpressed in B-NHL and is a prognostic factor. We hypothesized that the coexpression of KLF4 and YY1 may result from the transcriptional regulation of KLF4 by YY1. This hypothesis was tested in various experimental designs both in cell lines and tumor tissues derived from patients. Analysis of the B-NHL cell line Ramos revealed that both KLF4 and YY1 are overexpressed compared to normal B cells. The transfection of Ramos with siRNA YY1 showed significant inhibition of KLF4. In silico analyses of the KLF4 promoter identified the presence of four putative binding sites for YY1. We confirmed that the -126 site as the binding site for YY1 by CHIP analysis. We also used a reporter system of the KLF4 promoter and mutated the putative binding site for YY1 (-126) and confirmed it as an important site for the regulation of KLF4. The co-expressions of KLF4 and YY1 were examined in TMA of pediatric lymphomas and showed by IHC that all of the tumor tissues exhibited a positive correlation of the expressions of KLF4 and YY1 and the correlation was markedly significant in the Burkitt subtype. These correlations were consistent with the bioinformatics analyses due by ONCOMINE in several data base. KLF4 acts as a transcriptional activator of epithelial genes and as a repressor of mesenchymal genes. In addition, KLF4 suppresses the extrinsic apoptotic pathway by inhibiting the activation and cleavage of caspases (7, 9, and 3). Thus, the overexpression of KLF4 in lymphoma may be responsible, in part, in the pathogenesis, malignancy, and drug resistance. The putative function of KLF4 was examined by the use of chemical inhibitors for KLF4 (Kenpaullone) and inhibition of KLF4 resulted in the inhibition of cell proliferation and the spontaneous induction of apoptosis. The present findings suggest that both KLF4 and YY1 are prognostic biomarkers for pediatric lymphoma and are also potential therapeutic targets. Disclosures: No relevant conflicts of interest to declare.

scholarly journals Targeted Disruption of Mouse Yin Yang 1 Transcription Factor Results in Peri-Implantation Lethality

1999 ◽  
Vol 19 (10) ◽  
pp. 7237-7244 ◽  
Author(s):  
Mary E. Donohoe ◽  
Xiaolin Zhang ◽  
Lynda McGinnis ◽  
John Biggers ◽  
En Li ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Gene Targeting ◽  
Mouse Embryo ◽  
Mammalian Development ◽  
Targeted Disruption ◽  
Viral Oncoproteins ◽  
Yin Yang 1 ◽  
Yin Yang ◽  
Essential Function

ABSTRACT Yin Yang 1 (YY1) is a zinc finger-containing transcription factor and a target of viral oncoproteins. To determine the biological role of YY1 in mammalian development, we generated mice deficient for YY1 by gene targeting. Homozygosity for the mutated YY1 allele results in embryonic lethality in the mouse. YY1 mutants undergo implantation and induce uterine decidualization but rapidly degenerate around the time of implantation. A subset of YY1 heterozygote embryos are developmentally retarded and exhibit neurulation defects, suggesting that YY1 may have additional roles during later stages of mouse embryogenesis. Our studies demonstrate an essential function for YY1 in the development of the mouse embryo.

scholarly journals Interplay Between Heme Oxygenase-1 and the Multifunctional Transcription Factor Yin Yang 1 in the Inhibition of Intimal Hyperplasia

2010 ◽  
Vol 107 (12) ◽  
pp. 1490-1497 ◽  
Author(s):  
Konstanze Beck ◽  
Ben J. Wu ◽  
Jun Ni ◽  
Fernando S. Santiago ◽  
Kristine P. Malabanan ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Heme Oxygenase ◽  
Intimal Hyperplasia ◽  
Heme Oxygenase 1 ◽  
Yin Yang 1 ◽  
Yin Yang ◽  
Multifunctional Transcription Factor

scholarly journals The transcription factor Yin Yang 1 is an activator of BACE1 expression

2006 ◽  
Vol 96 (6) ◽  
pp. 1696-1707 ◽  
Author(s):  
Katrin Nowak ◽  
Christine Lange-Dohna ◽  
Ulrike Zeitschel ◽  
Albrecht Günther ◽  
Bernhard Lüscher ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Yin Yang 1 ◽  
Bace1 Expression ◽  
Yin Yang

scholarly journals Astrocyte-specific deletion of the transcription factor Yin Yang 1 in murine substantia nigra mitigates manganese-induced dopaminergic neurotoxicity

2020 ◽  
Vol 295 (46) ◽  
pp. 15662-15676 ◽  
Author(s):  
Edward Pajarillo ◽  
James Johnson ◽  
Asha Rizor ◽  
Ivan Nyarko-Danquah ◽  
Getinet Adinew ◽  
...  
Keyword(s):  
Transcription Factor ◽  
Substantia Nigra ◽  
Critical Role ◽  
Conditional Knockout ◽  
Motor Functions ◽  
Mn Toxicity ◽  
Protein Levels ◽  
Yin Yang 1 ◽  
Yin Yang

Manganese (Mn)-induced neurotoxicity resembles Parkinson's disease (PD), but the mechanisms underpinning its effects remain unknown. Mn dysregulates astrocytic glutamate transporters, GLT-1 and GLAST, and dopaminergic function, including tyrosine hydroxylase (TH). Our previous in vitro studies have shown that Mn repressed GLAST and GLT-1 via activation of transcription factor Yin Yang 1 (YY1). Here, we investigated if in vivo astrocytic YY1 deletion mitigates Mn-induced dopaminergic neurotoxicity, attenuating Mn-induced reduction in GLAST/GLT-1 expression in murine substantia nigra (SN). AAV5-GFAP-Cre-GFP particles were infused into the SN of 8-week–old YY1flox/flox mice to generate a region-specific astrocytic YY1 conditional knockout (cKO) mouse model. 3 weeks after adeno-associated viral (AAV) infusion, mice were exposed to 330 μg of Mn (MnCl2 30 mg/kg, intranasal instillation, daily) for 3 weeks. After Mn exposure, motor functions were determined in open-field and rotarod tests, followed by Western blotting, quantitative PCR, and immunohistochemistry to assess YY1, TH, GLAST, and GLT-1 levels. Infusion of AAV5-GFAP-Cre-GFP vectors into the SN resulted in region-specific astrocytic YY1 deletion and attenuation of Mn-induced impairment of motor functions, reduction of TH-expressing cells in SN, and TH mRNA/protein levels in midbrain/striatum. Astrocytic YY1 deletion also attenuated the Mn-induced decrease in GLAST/GLT-1 mRNA/protein levels in midbrain. Moreover, YY1 deletion abrogated its interaction with histone deacetylases in astrocytes. These results indicate that astrocytic YY1 plays a critical role in Mn-induced neurotoxicity in vivo, at least in part, by reducing astrocytic GLAST/GLT-1. Thus, YY1 might be a potential target for treatment of Mn toxicity and other neurological disorders associated with dysregulation of GLAST/GLT-1.

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