Role Of Yin Yang 1 Research Articles

The Role of YY1 in the Regulation of LAG-3 Expression in CD8 T Cells and Immune Evasion in Cancer: Therapeutic Implications

The treatment of cancers with immunotherapies has yielded significant milestones in recent years. Amongst these immunotherapeutic strategies, the FDA has approved several checkpoint inhibitors (CPIs), primarily Anti-Programmed Death-1 (PD-1) and Programmed Death Ligand-1/2 (PDL-1/2) monoclonal antibodies, in the treatment of various cancers unresponsive to immune therapeutics. Such treatments resulted in significant clinical responses and the prolongation of survival in a subset of patients. However, not all patients responded to CPIs, due to various mechanisms of immune resistance. One such mechanism is that, in addition to PD-1 expression on CD8 T cells, other inhibitory receptors exist, such as Lymphocyte Activation Gene 3 (LAG-3), T cell Immunoglobulin Mucin 3 (TIM3), and T cell immunoreceptor with Ig and ITIM domains (TIGIT). These inhibitory receptors might be active in the presence of the above approved CPIs. Clearly, it is clinically challenging to block all such inhibitory receptors simultaneously using conventional antibodies. To circumvent this difficulty, we sought to target a potential transcription factor that may be involved in the molecular regulation of more than one inhibitory receptor. The transcription factor Yin Yang1 (YY1) was found to regulate the expression of PD-1, LAG-3, and TIM3. Therefore, we hypothesized that targeting YY1 in CD8 T cells should inhibit the expression of these receptors and, thus, prevent the inactivation of the anti-tumor CD8 T cells by these receptors, by corresponding ligands to tumor cells. This strategy should result in the prevention of immune evasion, leading to the inhibition of tumor growth. In addition, this strategy will be particularly effective in a subset of cancer patients who were unresponsive to approved CPIs. In this review, we discuss the regulation of LAG-3 by YY1 as proof of principle for the potential use of targeting YY1 as an alternative therapeutic approach to preventing the immune evasion of cancer. We present findings on the molecular regulations of both YY1 and LAG-3 expressions, the direct regulation of LAG-3 by YY1, the various approaches to targeting YY1 to evade immune evasion, and their clinical challenges. We also present bioinformatic analyses demonstrating the overexpression of LAG-3, YY1, and PD-L1 in various cancers, their associations with immune infiltrates, and the fact that when LAG-3 is hypermethylated in its promoter region it correlates with a better overall survival. Hence, targeting YY1 in CD8 T cells will result in restoring the anti-tumor immune response and tumor regression. Notably, in addition to the beneficial effects of targeting YY1 in CD8 T cells to inhibit the expression of inhibitory receptors, we also suggest targeting YY1 overexpressed in the tumor cells, which will also inhibit PD-L1 expression and other YY1-associated pro-tumorigenic activities.

Role of YY1 in the Regulation of Anti-Apoptotic Gene Products in Drug-Resistant Cancer Cells.

Cancer is a leading cause of death among the various diseases encountered in humans. Cancer is not a single entity and consists of numerous different types and subtypes that require various treatment regimens. In the last decade, several milestones in cancer treatments were accomplished, such as specific targeting agents or revitalizing the dormant anti-tumor immune response. These milestones have resulted in significant positive clinical responses as well as tumor regression and the prolongation of survival in subsets of cancer patients. Hence, in non-responding patients and non-responding relapsed patients, cancers develop intrinsic mechanisms of resistance to cell death via the overexpression of anti-apoptotic gene products. In parallel, the majority of resistant cancers have been reported to overexpress a transcription factor, Yin Yang 1 (YY1), which regulates the chemo-immuno-resistance of cancer cells to therapeutic anticancer cytotoxic agents. The relationship between the overexpression of YY1 and several anti-apoptotic gene products, such as B-cell lymphoma 2 protein (Bcl-2), B-cell lymphoma extra-large (Bcl-xL), myeloid cell leukemia 1 (Mcl-1) and survivin, is investigated in this paper. The findings demonstrate that these anti-apoptotic gene products are regulated, in part, by YY1 at the transcriptional, epigenetic, post-transcriptional and translational levels. While targeting each of the anti-apoptotic gene products individually has been examined and clinically tested for some, this targeting strategy is not effective due to compensation by other overexpressed anti-apoptotic gene products. In contrast, targeting YY1 directly, through small interfering RNAs (siRNAs), gene editing or small molecule inhibitors, can be therapeutically more effective and generalized in YY1-overexpressed resistant cancers.

The role of transcription factor Yin Yang-1 in colorectal cancer.

Yin Yang-1 (YY1) is identified as a transcription factor with multiple functions. However, the role of YY1 in tumorigenesis remains controversial and its regulatory effects may depend upon not only cancer types, but also its interacting partners, chromatin structure, and the context in which it acts. It has been detected that YY1 was highly expressed in colorectal cancer (CRC). Intriguingly, many YY1-repressed genes exhibit tumor suppressive potential while YY1 silencing is related to chemotherapy resistance. Therefore, it is crucial to meticulously explore YY1 protein structure and the dynamic alteration of its interactome in each cancer type. This review attempts to describe the structure of YY1, summarize the mechanism that influence the expression level of YY1 and also highlight the recent advances in our understanding of regulatory insights of YY1 functions in CRC. Related studies were identified through scoping search of PubMed, Web of science, Scopus and Emhase concerning the terms of "colorectal cancer", colorectal carcinoma" or CRC with "YY1". The retrieval strategy included title, abstract, and keywords with no language limitations. All the included articles were categorized depending on the mechanisms they explored. In total, 170 articles were identified for further screening. After removing the duplication, not relevant outcomes and review articles, 34 were finally included in the review. Among them, 10 articles revealed the reasons of YY1 high expression in CRC, 13 articles explored YY1 function in CRC, and 11 articles fell into both aspects. In addition, we also summarized 10 clinical trials concerning the expression and activity of YY1 in various diseases, which offers a hint for future application. YY1 is highly expressed in CRC and broadly recognized as an oncogenic factor during the whole course of CRC. Sporadic controversial views are raised in term of CRC treatment, reminding us that future studies should take the influence of therapeutic regimens into concern.

YY1 was indispensable for the alleviation of quercetin on diabetic nephropathy-associated tubulointerstitial inflammation

BackgroundThe emergence of tubulointerstitial inflammation (TI) could accelerate the development of tubulointerstitial fibrosis (TIF) of diabetic nephropathy (DN). Yin Yang 1 (YY1) was a new pro-inflammatory mediator and became the important target of DN-related TIF. Quercetin performed an effective role in anti-inflammation and was probable to bind to YY1. However, the role of YY1 in quercetin's anti-inflammatory effect on DN-related TIF was uncovered. PurposeTo investigate the potential effect and mechanism of quercetin against DN-related TI. Study design and MethodsThe protein levels of YY1 were examined in the renal tubular epithelial cells (RTECs) of db/db mice and HG-cultured HK-2 cells. Molecular modeling studies and YY1 overexpression lentivirus vector were selected to further confirm the indispensable part of YY1 in quercetin's TI protection in vitro. Luciferase assay and chromatin immunoprecipitation (ChIP) assay were carried out to identify whether YY1 directly regulated IL-6/STAT3 signaling by binding to the IL-6 promoter in quercetin's TI protection in vitro. At last, the important role of YY1-mediated IL-6/STAT3 signaling in quercetin's TIF protection effect was further identified by using of YY1 overexpression lentivirus vector and IL-6 specific inhibitor tocilizumab. ResultsAlong with the alleviated tubulointerstitial injury by quercetin in the RTECs of db/db mice and HK-2 cells stimulated by HG, YY1-mediated IL-6/STAT-3 pathway involved in TI protection of quercetin in vivo and in vitro. Quercetin bound to YY1 and decreased its protein expression, and YY1 directly suppressed IL-6 transcription by bounding to its promoter, resulting in the alleviation of inflammation by inactivating of IL-6/STAT-3 pathway in vitro. YY1-mediated IL-6/STAT-3 pathway was also indispensable for the alleviation of quercetin on DN-associated TIF. ConclusionYY1 could not be absent from quercetin's anti-inflammatory effect on DN-associated TIF via alleviating IL-6/STAT-3 pathway mediated TI.

Localization and regulatory function of Yin Yang 1 (YY1) in chicken testis.

In mammals, Yin Yang 1 (YY1), a pervasively expressed transcription factor related to many biological processes as an activator or inhibitor of the transcription of various genes, plays a critical role in the development of male gonads and spermatogenesis. Although the role of YY1 on the development of male gonads and spermatogenesis in mammals has been reported, its function on chicken testis are yet to be clarified. In this study, we used immunofluorescence analysis to investigate the location of YY1 in chicken testis. In embryo testis, YY1 was detected in spermatogonia and Sertoli cells, while in adult testis, YY1 was shown to be expressed in spermatogenic cells and Sertoli cells, but not in spermatozoa. Furthermore, we investigated the regulatory functions of YY1 in chicken testicular Sertoli cells by combining overexpression with RNA-sequencing. Overexpression of YY1 in Sertoli cells revealed a total of 2955 differentially expressed genes involved in various biological processes, such as male gonad development and seminiferous tubule development. Overexpression of YY1 also caused significant differences in the expression of the androgen receptor gene and the inhibin βA gene, two major genes involved in the regulation of spermatogonia in Sertoli cells. These observations indicate that YY1 may regulate the development and function of the gonads by affecting the secretion of cytokines and hormones in Sertoli cells to mediate the production and differentiation of spermatogonia.

YY1 and CP2c in Unidirectional Spermatogenesis and Stemness.

Spermatogonial stem cells (SSCs) have stemness characteristics, including germ cell-specific imprints that allow them to form gametes. Spermatogenesis involves changes in gene expression such as a transition from expression of somatic to germ cell-specific genes, global repression of gene expression, meiotic sex chromosome inactivation, highly condensed packing of the nucleus with protamines, and morphogenesis. These step-by-step processes finally generate spermatozoa that are fertilization competent. Dynamic epigenetic modifications also confer totipotency to germ cells after fertilization. Primordial germ cells (PGCs) in embryos do not enter meiosis, remain in the proliferative stage, and are referred to as gonocytes, before entering quiescence. Gonocytes develop into SSCs at about 6 days after birth in rodents. Although chromatin structural modification by Polycomb is essential for gene silencing in mammals, and epigenetic changes are critical in spermatogenesis, a comprehensive understanding of transcriptional regulation is lacking. Recently, we evaluated the expression profiles of Yin Yang 1 (YY1) and CP2c in the gonads of E14.5 and 12-week-old mice. YY1 localizes at the nucleus and/or cytoplasm at specific stages of spermatogenesis, possibly by interaction with CP2c and YY1-interacting transcription factor. In the present article, we discuss the possible roles of YY1 and CP2c in spermatogenesis and stemness based on our results and a review of the relevant literature.

YY1/LncRNA GAS5 complex aggravates cerebral ischemia/reperfusion injury through enhancing neuronal glycolysis

Yin-Yang 1 (YY1) has been identified as playing critical roles in multiple diseases. However, little is known regarding its roles and mechanisms in cerebral ischemia/reperfusion (I/R) injury. This study is aimed to explore the roles of YY1 in regulating neuronal apoptosis in cerebral I/R injury and its underlying mechanisms. Primary mouse cerebral cortical neurons were isolated and subjected to OGD/R to mimic cerebral I/R injury in vitro. The roles of YY1 on OGD/R-induced neuronal injury were investigated by performing western blotting, quantitative real-time polymerase chain reaction, TUNEL, RNA-binding protein immunoprecipitation, chromatin immunoprecipitation, chromatin isolation by RNA purification assay, glucose uptake assay, lactate production assay, and extracellular acidification rate assay. YY1-binding long non-coding RNAs (LncRNAs) in neurons subjected to OGD/R were identified by RIP and RNA sequencing. The roles of YY1 on cerebral I/R in vivo were detected by assessing neuronbehaviour, infarct size, and neuronal apoptosis. We found that YY1 expression is downregulated, and LncRNA GAS5 is upregulated in neurons subjected to OGD/R. OGD/R treatment promotes YY1 interacting with GAS5 in neurons, and YY1 negatively regulates GAS5 expression by binding to GAS5 promoter to repress its transcription. Besides, YY1 and GAS5 bind to the same region of PFKFB3 promoter to promote PFKFB3 expression and strengthen neuronal glycolysis, resulting in aggravating OGD/R-induced neuronal apoptosis. Knockdown of YY1 or GAS5 protects against I/R-induced ischemic brain damage and improves overall neurological functions in vivo. Overall, YY1 interacts with LncRNA GAS5 to promote PFKFB3 transcription to enhance neuronal glycolysis, resulting in aggravating cerebral I/R injury.

YY1 regulates cancer cell immune resistance by modulating PD-L1 expression.

Recent advances in the treatment of various cancers have resulted in the adaptation of several novel immunotherapeutic strategies. Notably, the recent intervention through immune checkpoint inhibitors has resulted in significant clinical responses and prolongation of survival in patients with several therapy-resistant cancers (melanoma, lung, bladder, etc.). This intervention was mediated by various antibodies directed against inhibitory receptors expressed on cytotoxic T-cells or against corresponding ligands expressed on tumor cells and other cells in the tumor microenvironment (TME). However, the clinical responses were only observed in a subset of the treated patients; it was not clear why the remaining patients did not respond to checkpoint inhibitor therapies. One hypothesis stated that the levels of PD-L1 expression correlated with poor clinical responses to cell-mediated anti-tumor immunotherapy. Hence, exploring the underlying mechanisms that regulate PD-L1 expression on tumor cells is one approach to target such mechanisms to reduce PD-L1 expression and, therefore, sensitize the resistant tumor cells to respond to PD-1/PD-L1 antibody treatments. Various investigations revealed that the overexpression of the transcription factor Yin Yang 1 (YY1) in most cancers is involved in the regulation of tumor cells' resistance to cell-mediated immunotherapies. We, therefore, hypothesized that the role of YY1 in cancer immune resistance may be correlated with PD-L1 overexpression on cancer cells. This hypothesis was investigated and analysis of the reported literature revealed that several signaling crosstalk pathways exist between the regulations of both YY1 and PD-L1 expressions. Such pathways include p53, miR34a, STAT3, NF-kB, PI3K/AKT/mTOR, c-Myc, and COX-2. Noteworthy, many clinical and pre-clinical drugs have been utilized to target these above pathways in various cancers independent of their roles in the regulation of PD-L1 expression. Therefore, the direct inhibition of YY1 and/or the use of the above targeted drugs in combination with checkpoint inhibitors should result in enhancing the cell-mediated anti-tumor cell response and also reverse the resistance observed with the use of checkpoint inhibitors alone.

Involvement of Yin Yang 1 (YY1) Expression in T-Cell Subsets Differentiation and Their Functions: Implications in T Cell-Mediated Diseases.

The transcription factor Yin Yang 1 (YY1) has been implicated in embryogenesis, cell differentiation, organ development, and regulation of T cell-mediated immune diseases. YY1 has been reported to act as an activator or repressor, or both, of various genes depending on the nature of the tissue and their context. Although the roles of YY1 in both pathogenesis and progression of tumors has been the subject of many reports, the roles of YY1 in the immune system are not as well known. In this review, we examine the literature on the role of YY1 in both the differentiation and the development of various subsets of the T lymphocytes and examined its molecular role in these areas. We examined the role of YY1 in the thymus for the development of both CD4 and CD8 T lymphocytes, the various CD4 subsets, Th1, Th2, Th17, and Treg. Our analyses revealed that the presence of YY1 is necessary for maturation and proliferation of the αβ lineage through its role in mediating the apoptotic pathway. Moreover, in differentiation of T cell subsets, YY1 controls the expression of the Th2 master regulator GATA3, the Treg inducer Foxp3, as well as IL-12 expression, which is important in regulating production of Th1 cytokines. Furthermore, the role of YY1 in the Th17 signaling pathway has not been fully identified, although recent studies have suggested that differentiation of Th17 involves synergistic action of YY1 and STAT3. The previously mentioned findings strongly suggest that the role of YY1 in T cells is critical in both their normal differentiation and the induction of T cell-mediated autoimmune diseases. Clearly, such findings suggest the potential therapeutic applications of YY1 inhibitors to alleviate its role in autoimmune diseases.

Yin Yang 1 facilitates hepatocellular carcinoma cell lipid metabolism and tumor progression by inhibiting PGC-1β-induced fatty acid oxidation.

Lipid accumulation is a driving force in tumor development, as it provides tumor cells with both energy and the building blocks of phospholipids for construction of cell membranes. Aberrant homeostasis of lipid metabolism has been observed in various tumors; however, the molecular mechanism has not been fully elucidated.Methods: Yin yang 1 (YY1) expression in hepatocellular carcinoma (HCC) was analyzed using clinical specimens, and its roles in HCC in lipid metabolism were examined using gain- and loss-of function experiments. The mechanism of YY1 regulation on peroxisome proliferator-activated receptor gamma coactivator-1β (PGC-1β) and its downstream genes medium-chain acyl-CoA dehydrogenase (MCAD) and long-chain acyl-CoA dehydrogenase (LCAD) were investigated using molecular biology and biochemical methods. The role of YY1/ PGC-1β axis in hepatocarcinogenesis was studied using xenograft experiment.Results: This study showed that YY1 suppresses fatty acid β-oxidation, leading to increase of cellular triglyceride level and lipid accumulation in HCC cells, and subsequently induction of the tumorigenesis potential of HCC cells. Molecular mechanistic study revealed that YY1 blocks the expression of PGC-1β, an activator of fatty acid β-oxidation, by directly binding to its promoter; and thus downregulates PGC-1β/MCAD and PGC1-β/LCAD axis. Importantly, we revealed that YY1 inhibition on PGC-1β occurs irrespective of the expression of hypoxia-inducible factor-1α (HIF1-α), enabling it to promote lipid accumulation under both normoxic and hypoxic conditions.Conclusion: Our study reveals the critical role of YY1/PGC-1β axis in HCC cell lipid metabolism, providing novel insight into the molecular mechanisms associated with tumor cell lipid metabolism, and a new perspective regarding the function of YY1 in tumor progression. Thus, our study provides evidences regarding the potential of YY1 as a target for lipid metabolism-based anti-tumor therapy.

Transcription Factor YY1 Promotes Cell Proliferation by Directly Activating the Pentose Phosphate Pathway.

Tumor cells alter their metabolism to meet their demand for macromolecules and support a high rate of proliferation as well as cope with oxidative stress. The transcription factor yin yang 1 (YY1) is upregulated in various types of tumors and is crucial for tumor cell proliferation and metastasis. However, its role in tumor cell metabolic reprogramming is poorly understood. Here, we show that YY1 alters tumor cell metabolism by activating glucose-6-phosphate dehydrogenase (G6PD), the rate-limiting enzyme in the pentose phosphate pathway. By stimulating the pentose phosphate pathway, YY1 enhanced production of nucleotides and DNA synthesis, decreased intracellular reactive oxygen species levels, and promoted antioxidant defense by supplying increased reducing power in the form of NADPH. Importantly, YY1-mediated regulation of the pentose phosphate pathway in tumor cells occurred not through p53, but rather through direct activation of G6PD transcription by YY1. Regulation of pentose phosphate pathway activity through G6PD was strongly related to YY1-induced proliferation of tumor cells and tumorigenesis. Together, our results describe a novel role for YY1 in regulating G6PD in a p53-independent manner, which links its function in tumorigenesis to metabolic reprogramming in tumor cells.Significance: This study reveals a novel role for YY1 in regulating G6PD and activating the pentose phosphate pathway, linking its function in tumorigenesis to metabolic reprogramming. Cancer Res; 78(16); 4549-62. ©2018 AACR.

YY1 Expression Is Sufficient for the Maintenance of Cardiac Progenitor Cell State.

During cardiac development, DNA binding transcription factors and epigenetic modifiers regulate gene expression in cardiac progenitor cells (CPCs). We have previously shown that Yin Yang 1 (YY1) is essential for the commitment of mesodermal precursors into CPCs. However, the role of YY1 in the maintenance of CPC phenotype and their differentiation into cardiomyocytes is unknown. In this study, we found, by genome-wide transcriptional profiling and phenotypic assays, that YY1 overexpression prevents cardiomyogenic differentiation and maintains the proliferative capacity of CPCs. We show further that the ability of YY1 to regulate CPC phenotype is associated with its ability to modulate histone modifications specifically at a developmentally critical enhancer of Nkx2-5 and other key cardiac transcription factor such as Tbx5. Specifically, YY1 overexpression helps to maintain markers of gene activation such as the acetylation of histone H3 at lysine 9 (H3K9Ac) and lysine 27 (H3K27Ac) as well as trimethylation at lysine 4 (H3K4Me3) at the Nkx2-5 cardiac enhancer. Furthermore, transcription factors associated proteins such as PoIII, p300, and Brg1 are also enriched at the Nkx2-5 enhancer with YY1 overexpression. The biological activities of YY1 in CPCs appear to be cell autonomous, based coculture assays in differentiating embryonic stem cells. Altogether, these results demonstrate that YY1 overexpression is sufficient to maintain a CPC phenotype through its ability to sustain the presence of activating epigenetic/chromatin marks at key cardiac enhancers. Stem Cells 2017;35:1913-1923.

The Role of Transcription Factor YY1 in the Biology of Cancer.

The transcription factor Yin Yang 1 (YY1) is a ubiquitously expressed protein involved in several biological functions, including embryogenesis, differentiation, replication, and cellular proliferation. YY1 can both activate and repress transcription depending on its interactions with other transcription factors and co-factors. It affects the transcription of a large number of mammalian and viral genes. In this review, we focus on the role of YY1 in cancer biology, including its expression, function, regulation by other upstream factors, and some of its more significant downstream effectors. We also discuss its context-dependent and tumor-specific role in human cancer progression, roles as a prognostic marker, and how its interactions with other cancer-associated factors can be exploited to develop novel targeted therapies.

Yin Yang 1 Dynamically Regulates Antiviral Innate Immune Responses During Viral Infection

Background/Aims: Type I interferon (IFN-1) production and IFN-1 signaling play critical roles in the host antiviral innate immune responses. Although transcription factor Yin Yang 1 (YY1) has been reported to have a dual activator/repressor role during the regulation of interferon beta (IFN-β) promoter activity, the roles of YY1 in the regulation of upstream signaling pathways leading to IFN-1 induction and IFN-1 signaling during viral infection remain to be elucidated. Methods: The roles of YY1 in IFN-1 production and IFN-1 signaling were investigated using immunoblotting, real-time PCR, small interfering RNA (siRNA)-mediated YY1 knockdown, YY1 overexpression by transient transfection, and co-immunoprecipitation, using mouse cells. Results: YY1 was shown to interact with STAT1 in the absence of viral infection. Following viral infection, YY1 protein expression levels were decreased. YY1 knockdown led to a considerable downregulation of phosphorylated (p) TBK1 and pIRF3 expressions, while YY1 overexpression significantly upregulated pTBK1 and pIRF3 expression levels and promoted virus-induced IFN-β production. Additionally, YY1 knockdown led to a significant upregulation of pSTAT1, pSTAT2 and antiviral interferon-stimulated genes, and inhibited viral replication. Conclusion: We demonstrated here that YY1 interacts with STAT1 and dynamically regulates the induction of IFN-1 production and activation of IFN-1 signaling in different stages during viral infection.

YY1 in Cell Differentiation and Tissue Development.

Yin Yang1 (YY1) is a ubiquitous expressed transcription factor that modulates a variety of biologic processes with prominent roles in cellular differentiation and tissue development. Recent advances in molecular biology, mouse genetics, and particularly high-throughput sequencing have greatly enhanced our understanding of YY1 functions and underlying mechanisms in regulating transcription and epigenetics. In this review, we summarize findings on the roles of YY1 in cell differentiation and tissue development, in particular in muscle, nerve, and immune cells/tissues.

Yin Yang 1 (YY1) Acting Primarily As an Oncogene and Rarely As a Tumor Suppressor in Distinct Hematological Malignancies: Prognostic and Therapeutic Implications

Yin Yang 1 (YY1) is a transcription factor that is ubiquitously expressed in many normal and cancerous tissues. This transcription factor was reported to have contradictory functions, consistent with its name, and it was shown to either activate and/or repress several gene products. The role of YY1 in cancer was initially reported to be overexpressed in a large number of solid cancers, and its overexpression was suggested to be of prognostic significance (Shi et al, Curr Cancer Drug Targets 2015;15:145-57). In addition, YY1 was also shown to be a pivotal factor in both drug and immune resistance, as well as it plays an important role in invasion and metastasis (Bonavida and Baritaki, Critical Reviews in Oncogenesis 2011;16:211-226). The reported protein expression and mRNA expressions derived from Oncomine datasets were examined to assess the functions of YY1 in a large number of hematological malignancies (Bonavida and Kaufhold, Pharmacol Ther 2015;150:149-68). However, YY1 expression was not reported in all cancer types. Our preliminary findings suggested that YY1 may act either as an oncogene or as a tumor suppressor in distinct types of hematological malignancies. In multiple myeloma (MM), YY1 protein overexpression was reported and shown to be complexed with the NF-κB subunit RelA. In addition, computational analysis revealed that increased YY1 transcript levels were observed in MM. These findings suggested that YY1 may act as an oncogene in MM, and the supporting data demonstrated that knockdown of YY1 resulted in cell death of MM cell lines. Further bioinformatic analyses showed that YY1 was overexpressed in AML patient-derived tumor tissues. In contrast to AML, bioinformatics analysis revealed that YY1 mRNA was not upregulated in chronic lymphocytic leukemia (CLL) and no significant differences were observed when compared to normal tissues. Clearly, these findings suggested that YY1 may be acting as an oncogene in AML but as a tumor suppressor in CLL. In B-cell non-Hodgkin lymphoma (NHL), the overexpression of YY1 at both mRNA and protein levels suggests its involvement in the malignant transformation. Overall, these data strongly support the notion of the oncogenic role played by the transcription factor YY1 in the majority of hematological malignancies. Accordingly, we suggest that YY1 may have important implications as a therapeutic target and as a prognostic biomarker in hematological malignancies. DisclosuresNo relevant conflicts of interest to declare.

Polycomb recruitment at the Class II transactivator gene.

The Class II Transactivator (CIITA) is the master regulator of Major Histocompatibility Class II (MHC II) genes. Transcription of CIITA through the IFN-γ inducible CIITA promoter IV (CIITA pIV) during activation is characterized by a decrease in trimethylation of histone H3 lysine 27 (H3K27me3), catalyzed by the histone methyltransferase Enhancer of Zeste Homolog 2 (EZH2). While EZH2 is the known catalytic subunit of the Polycomb Repressive Complex 2 (PRC2) and is present at the inactive CIITA pIV, the mechanism of PRC2 recruitment to mammalian promoters remains unknown. Here we identify two DNA-binding proteins, which interact with and regulate PRC2 recruitment to CIITA pIV. We demonstrate Yin Yang 1 (YY1) and Jumonji domain containing protein 2 (JARID2) are binding partners along with EZH2 in mammalian cells. Upon IFN-γ stimulation, YY1 dissociates from CIITA pIV while JARID2 binding to CIITA pIV increases, suggesting novel roles for these proteins in regulating expression of CIITA pIV. Knockdown of YY1 and JARID2 yields decreased binding of EZH2 and H3K27me3 at CIITA pIV, suggesting important roles for YY1 and JARID2 at CIITA pIV. JARID2 knockdown also results in significantly elevated levels of CIITA mRNA upon IFN-γ stimulation. This study is the first to identify novel roles of YY1 and JARID2 in the epigenetic regulation of the CIITA pIV by recruitment of PRC2. Our observations indicate the importance of JARID2 in CIITA pIV silencing, and also provide a novel YY1-JARID2-PRC2 regulatory complex as a possible explanation of differential PRC2 recruitment at inducible versus permanently silenced genes.

Abstract 5202: Yin Yang 1 is a target of miR-34 family and contributes to gastric carcinogenesis

Abstract Gastric cancer is one of the most common cancers and the second leading cause of cancer-related death worldwide. Transcription factor Yin Yang 1 (YY1) is a multi-functional protein and plays either oncogenic or tumor-suppressive roles in tumor development and progression. Herein, we investigated the role of YY1 in tumorigenesis of gastric cancer cells. Results showed that the forced expression of YY1 contributed to gastric carcinogenesis of SC-M1 cells. Whereas, the knockdown of endogenous YY1 suppressed tumorigenesis of SC-M1 cells. Additionally, the 3′-untranslated region (3′-UTR) of YY1 mRNA was the target of microRNA-34 (miR-34) family consisting of miR-34a, miR-34b, and miR-34c. The ectopic expression of miR-34 family down-regulated YY1 levels in gastric cancer cells. Endogenous YY1 expression was negatively correlated with miR-34b and miR-34c levels in gastric cancer cells. The overexpression of miR-34 family suppressed gastric carcinogenesis through down-regulation of YY1 in gastric cancer cells. Alternatively, the knockdown of endogenous miR-34 family promoted gastric carcinogenesis via up-regulation of YY1 in gastric cancer cells. The miR-34 family also regulated the xenografted tumor growth and lung metastasis of SC-M1 cells through YY1 in vivo. Taken together, these results suggest that miR-34 family-YY1 axis plays an important role in the control of gastric carcinogenesis. Citation Format: An-Ming Wang, Tzu-Ting Huang, Kai-Wen Hsu, Chin-Wen Chi, Tien-Shun Yeh. Yin Yang 1 is a target of miR-34 family and contributes to gastric carcinogenesis. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 5202. doi:10.1158/1538-7445.AM2014-5202

Role of YY1 in the pathogenesis of prostate cancer and correlation with bioinformatic data sets of gene expression.

Current treatments of various cancers include chemotherapy, radiation, surgery, immunotherapy, and combinations. However, there is a need to develop novel diagnostic and therapeutic treatments for unresponsive patients. These may be achieved by the identification of novel diagnostic and prognostic biomarkers which will help in the stratification of patients' initial responses to particular treatments and circumvent resistance, relapses, metastasis, and death. We have been investigating human prostate cancer as a model tumor. We have identified Yin Yang 1 (YY1), a dysregulated transcription factor, whose overexpression correlated with tumor progression as well as in the regulation of drug resistance and the development of EMT. YY1 expression is upregulated in human prostate cancer cell lines and tissues. We postulated that YY1 may be a potential biomarker in prostate cancer for patients' stratification as well as a novel target for therapeutic intervention. We used Bioinformatic gene RNA array datasets for the expression of YY1 in prostate tumor tissues as compared to normal tissues. Interestingly, variations on the expression levels of YY1 mRNA in prostate cancer were reported by different investigators. This mini review summarizes the current reported studies and Bioinformatic analyses on the role of YY1 in the pathogenesis of prostate cancer.

Yin Yang-1 suppresses invasion and metastasis of pancreatic ductal adenocarcinoma by downregulating MMP10 in a MUC4/ErbB2/p38/MEF2C-dependent mechanism.

BackgroundIncreasing evidence indicates an important role of transcription factor Yin Yang-1 (YY1) in human tumorigenesis. However, its function in cancer remains controversial and the relevance of YY1 to pancreatic ductal adenocarcinoma (PDAC) remains to be clarified.MethodsIn this study, we detected YY1 expression in clinical PDAC tissue samples and cell lines using quantitative RT-PCR, immunohistochemistry and western blotting. We also detected MUC4 and MMP10 mRNA levels in 108 PDAC samples using qRT-PCR and analyzed the correlations between YY1 and MUC4 or MMP10 expression. The role of YY1 in the proliferation, invasion and metastatic abilities of PDAC cells in vitro was studied by CCK-8 assay, cell migration and invasion assays. In vivo pancreatic tumor growth and metastasis was studied by a xenogenous subcutaneously implant model and a tail vein metastasis model. The potential mechanisms underlying YY1 mediated tumor progression in PDAC were explored by digital gene expression (DGE) sequencing, signal transduction pathways blockage experiments and luciferase assays. Statistical analysis was performed using the SPSS 15.0 software.ResultsWe found that the expression of YY1 in PDACs was higher compared with their adjacent non-tumorous tissues and normal pancreas tissues. However, PDAC patients with high level overexpression of YY1 had better outcome than those with low level overexpression. YY1 expression levels were statistically negatively correlated with MMP10 expression levels, but not correlated with MUC4 expression levels. YY1 overexpression suppressed, whereas YY1 knockdown enhanced, the proliferation, invasion and metastatic properties of BXPC-3 cells, both in vitro and in vivo. YY1 suppresses invasion and metastasis of pancreatic cancer cells by downregulating MMP10 in a MUC4/ErbB2/p38/MEF2C-dependent mechanism.ConclusionsThe present study suggested that YY1 plays a negative role, i.e. is a tumor suppressor, in PDAC, and may become a valuable diagnostic and prognostic marker of PDAC.