Prognostic significance of YY1 protein expression and mRNA levels by bioinformatics analysis in human cancers: A therapeutic target

Bonavida, Benjamin; Kaufhold, Samantha

doi:10.1016/j.pharmthera.2015.01.011

Cited by 56 publications

(36 citation statements)

References 139 publications

(197 reference statements)

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“…In agreement, we have previously reported a dysregulated NF-κB/YY1/Snail/RKIP/PTEN loop detected in many cancers and showed that it promotes cell survival, proliferation, induces an epithelial to mesenchymal transition (EMT), potentiates invasion and metastasis, maintains drug/immune resistance, promotes anti-apoptotic mechanisms, and regulates the cancer stem cell phenotype [11, 12]. In short, high RKIP expression inhibits NF-κB, thereby inhibiting Snail, YY1, AKT while inducing PTEN and pro-apoptotic factors.…”

Section: Introductionsupporting

confidence: 77%

Overexpression of RKIP and its cross-talk with several regulatory gene products in multiple myeloma

Shvartsur

Givechian

Garbán

et al. 2017

J Exp Clin Cancer Res

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Multiple myeloma (MM) is a clonal plasma-cell neoplastic disorder arising from an indolent premalignant disease known as monoclonal gammopathy of undetermined significance (MGUS). MM is a biologically complex heterogeneous disease reflected by its variable clinical responses of patients receiving the same treatment. Therefore, a molecular identification of stage-specific biomarkers will support a more individualized precise diagnostic/prognostic approach, an effective therapeutic regime, and will assist in the identification of novel therapeutic molecular targets. The metastatic suppressor/anti-resistance factor Raf-1 kinase inhibitor protein (RKIP) is poorly expressed in the majority of cancers and is often almost absent in metastatic tumors. RKIP inhibits the Raf/MEK/ERK1/2 and the NF-κB pathways. Whereby all tumors examined exhibited low levels of RKIP, in contrast, our recent findings demonstrated that RKIP is overexpressed primarily in its inactive phosphorylated form in MM cell lines and patient-derived tumor tissues. The underlying mechanism of RKIP overexpression in MM, in contrast to other tumors, is not known. We examined transcriptomic datasets on Oncomine platform (Life Technologies) for the co-expression of RKIP and other gene products in both pre-MM and MM. The transcription of several gene products was found to be either commonly overexpressed (i.e., RKIP, Bcl-2, and DR5) or underexpressed (i.e., Bcl-6 and TNFR2) in both pre-MM and MM. Noteworthy, a significant inverse correlation of differentially expressed pro-apoptotic genes was observed in pre-MM: overexpression of Fas and TNF-α and underexpression of YY1 versus expression of anti-apoptotic genes in MM: overexpression of YY1 and underexpression of Fas and TNF-α. Based on the analysis on mRNA levels and reported studies on protein levels of the above various genes, we have constructed various schemes that illustrate the possible cross-talks between RKIP (active/inactive) and the identified gene products that underlie the mechanism of RKIP overexpression in MM. Clearly, such cross-talks would need to be experimentally validated in both MM cell lines and patient-derived tumor tissues. If validated, the differential molecular signatures between pre-MM and MM might lead to a more precise diagnosis/prognosis of the disease and disease stages and will also identify novel molecular therapeutic targets for pre-MM and MM.Electronic supplementary materialThe online version of this article (doi:10.1186/s13046-017-0535-z) contains supplementary material, which is available to authorized users.

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Section: Introductionsupporting

confidence: 77%

Overexpression of RKIP and its cross-talk with several regulatory gene products in multiple myeloma

Shvartsur

Givechian

Garbán

et al. 2017

J Exp Clin Cancer Res

Self Cite

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“…However, as data on its prognostic significance has become available for more human cancers, YY1′s role in tumor progression has become more controversial [32]. Why YY1′s correlation with clinical outcomes is inconsistent among different cancers is unknown.…”

Section: Discussionmentioning

confidence: 99%

“…There is increasing evidence that YY1 is important in cancer development. Overexpression of YY1 has been observed in various cancers, including prostate cancer, ovarian cancer, and colon cancer [30–32]. The role of YY1 in cancer is due to its ability to modulate many genes involved in cancer development and progression, such as c-myc , c-fos , ERBB2 , CEBPA , and p53 [26, 33–34].…”

Section: Introductionmentioning

confidence: 99%

Diagnostic and prognostic relevance of CP2c and YY1 expression in hepatocellular carcinoma

et al. 2017

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Recent studies have demonstrated an oncogenic role of the transcription factor (TF) CP2c in hepatocellular carcinoma (HCC) based on a strong correlation between CP2c expression, tumor grade, and aggressiveness. We recently found that CP2c directly interacts with another TF, YY1, which is also overexpressed in multiple cancers, including HCC. To evaluate if these proteins are co-regulated in carcinogenesis, we analyzed the expression of CP2c and YY1 in HCC (n = 136) tissues and examined the correlation between their expression and clinicopathological characteristics of HCC. Receiver operating characteristic analysis exhibited the validity of CP2c and nuclear YY1 expression as a diagnostic factor in HCC tissues. High expression of CP2c was significantly correlated with patient age, and higher histological grade, American Joint Committee on Cancer (AJCC) stage, and small and large vessel invasion in HCC tissues, whereas high expression of nuclear YY1 was significantly associated with higher AJCC stage and small vessel invasion. In univariate and multivariate analyses, high expression of CP2c was significantly correlated with disease free survival (DFS), indicating that CP2c expression is an independent prognostic factor for DFS in HCC patients. Patients with high expression of both CP2c and nuclear YY1 usually had a shorter median survival time and worse DFS prognosis than other patients, suggesting that combined detection of CP2c and nuclear YY1 is a useful prognostic marker in HCC patients.

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“…YY1 is able to activate or repress transcription through displacement, functional interference, interactions with corepressors, chromatin remodeling, direct activation, cofactor‐induced inhibition and coactivator recruitment as reviewed in Gordon et al . YY1 has also been the subject of a number of other excellent reviews in regard to relaying oncogenic signals, its roles as a prognostic marker and control of epithelial‐to‐mesenchymal transition and imprinted genes …”

mentioning

confidence: 99%

The Yin and Yang of YY1 in tumor growth and suppression

Khachigian

2018

Intl Journal of Cancer

132

106

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Yin Yang-1 (YY1) is a zinc finger protein and member of the GLI-Kruppel family that can activate or inactivate gene expression depending on interacting partners, promoter context and chromatin structure, and may be involved in the transcriptional control of ∼10% of the total mammalian gene set. A growing body of literature indicates that YY1 is overexpressed in multiple cancer types and that increased YY1 levels correlate with poor clinical outcomes in many cancers. However, the role of YY1 in the promotion or suppression of tumor growth remains controversial and its regulatory effects may be tumor cell type dependent at least in experimental systems. The molecular mechanisms responsible for the apparently conflicting roles of YY1 are not yet fully elucidated. This review highlights recent advances in our understanding of regulatory insights involving YY1 function in a range of cancer types. For example, YY1's roles in tumor growth involve stabilization of hypoxia-inducible factor HIF-1α in a p53 independent manner, negative regulation of miR-9 transcription, control of MYCT1 transcription, a novel miR-193a-5p-YY1-APC axis, intracellular ROS and mitochondrial superoxide generation, p53 reduction and EGFR activation, control of genes associated with mitochondrial energy metabolism and miRNA regulatory networks involving miR-7, miR-9, miR-34a, miR-186, miR-381, miR-584-3p and miR-635. On the other hand, tumor suppressor roles of YY1 appear to involve YY1 stimulation of tumor suppressor BRCA1, increased Bax transcription and apoptosis involving cytochrome c release and caspase-3/-7 cleavage, induction of heme oxygenase-1, inhibition of pRb phosphorylation and p21 binding to cyclin D1 and cdk4, reduced expression of long noncoding RNA of SOX2 overlapping transcript, and MUC4/ErbB2/p38/MEF2C-dependent downregulation of MMP-10. YY1 expression is associated with that of cancer stem cell markers SOX2, BMI1 and OCT4 across many cancers suggesting multidynamic regulatory control and groups of cancers with distinct molecular signatures. Greater understanding of the mechanistic roles of YY1 will in turn lead to the development of more specific approaches to modulate YY1 expression and activity with therapeutic potential.

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Prognostic significance of YY1 protein expression and mRNA levels by bioinformatics analysis in human cancers: A therapeutic target

Cited by 56 publications

References 139 publications

Overexpression of RKIP and its cross-talk with several regulatory gene products in multiple myeloma

Overexpression of RKIP and its cross-talk with several regulatory gene products in multiple myeloma

Diagnostic and prognostic relevance of CP2c and YY1 expression in hepatocellular carcinoma

The Yin and Yang of YY1 in tumor growth and suppression

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