Yin Yang 1 Expression Research Articles

Hybrid 18F-FDG-PET/MRI Measurement of Standardized Uptake Value Coupled with Yin Yang 1 Signature in Metastatic Breast Cancer. A Preliminary Study.

Purpose: Detection of breast cancer (BC) metastasis at the early stage is important for the assessment of BC progression status. Image analysis represents a valuable tool for the management of oncological patients. Our preliminary study combined imaging parameters from hybrid 18F-FDG-PET/MRI and the expression level of the transcriptional factor Yin Yang 1 (YY1) for the detection of early metastases. Methods: The study enrolled suspected n = 217 BC patients that underwent 18F-FDG-PET/MRI scans. The analysis retrospectively included n = 55 subjects. n = 40 were BC patients and n = 15 imaging-negative female individuals were healthy subjects (HS). Standard radiomics parameters were extracted from PET/MRI image. RNA was obtained from peripheral blood mononuclear cells and YY1 expression level was evaluated by real time reverse transcription polymerase chain reactions (qRT-PCR). An enzyme-linked immuosorbent assay (ELISA) was used to determine the amount of YY1 serum protein. Statistical comparison between subgroups was evaluated by Mann-Whitney U and Spearman’s tests. Results: Radiomics showed a significant positive correlation between Greg-level co-occurrence matrix (GLCM) and standardized uptake value maximum (SUVmax) (r = 0.8 and r = 0.8 respectively) in BC patients. YY1 level was significant overexpressed in estrogen receptor (ER)-positive/progesteron receptor-positive/human epidermal growth factor receptor2-negative (ER+/PR+/HER2-) subtype of BC patients with synchronous metastasis (SM) at primary diagnosis compared to metachronous metastasis (MM) and HS (p < 0.001) and correlating significantly with 18F-FDG-uptake parameter (SUVmax) (r = 0.48). Conclusions: The combination of functional 18F-FDG-PET/MRI parameters and molecular determination of YY1 could represent a novel integrated approach to predict synchronous metastatic disease with more accuracy than 18F-FDG-PET/MRI alone.

Nitric Oxide-Mediated Enhancement and Reversal of Resistance of Anticancer Therapies.

In the last decade, immune therapies against human cancers have emerged as a very effective therapeutic strategy in the treatment of various cancers, some of which are resistant to current therapies. Although the clinical responses achieved with many therapeutic strategies were significant in a subset of patients, another subset remained unresponsive initially, or became resistant to further therapies. Hence, there is a need to develop novel approaches to treat those unresponsive patients. Several investigations have been reported to explain the underlying mechanisms of immune resistance, including the anti-proliferative and anti-apoptotic pathways and, in addition, the increased expression of the transcription factor Yin-Yang 1 (YY1) and the programmed death ligand 1 (PD-L1). We have reported that YY1 leads to immune resistance through increasing HIF-1α accumulation and PD-L1 expression. These mechanisms inhibit the ability of the cytotoxic T-lymphocytes to mediate their cytotoxic functions via the inhibitory signal delivered by the PD-L1 on tumor cells to the PD-1 receptor on cytotoxic T-cells. Thus, means to override these resistance mechanisms are needed to sensitize the tumor cells to both cell killing and inhibition of tumor progression. Treatment with nitric oxide (NO) donors has been shown to sensitize many types of tumors to chemotherapy, immunotherapy, and radiotherapy. Treatment of cancer cell lines with NO donors has resulted in the inhibition of cancer cell activities via, in part, the inhibition of YY1 and PD-L1. The NO-mediated inhibition of YY1 was the result of both the inhibition of the upstream NF-κB pathway as well as the S-nitrosylation of YY1, leading to both the downregulation of YY1 expression as well as the inhibition of YY1-DNA binding activity, respectively. Also, treatment with NO donors induced the inhibition of YY1 and resulted in the inhibition of PD-L1 expression. Based on the above findings, we propose that treatment of tumor cells with the combination of NO donors, at optimal noncytotoxic doses, and anti-tumor cytotoxic effector cells or other conventional therapies will result in a synergistic anticancer activity and tumor regression.

Activation of AK005401 aggravates acute ischemia/reperfusion mediated hippocampal injury by directly targeting YY1/FGF21.

Ischemia exerts a negative impact on mitochondrial function, which ultimately results in neuronal damage via alterations in gene transcription and protein expression. Long non- coding RNAs (LncRNAs) play pivotal roles in the regulation of target protein expression and gene transcription. In the present study, we observed the effect of an unclassical LncRNA AK005401on ischemia/reperfusion (I/R) ischemia-mediated hippocampal injury and investigated the regulatory role of fibroblast growth factor 21 (FGF21) and Yin Yang 1 (YY1). C57Black/6 mice were subjected to I/R using the bilateral common carotid clip reperfusion method, and AK005401 siRNA oligos were administered via intracerebroventricular injection. HT22 cells were used to establish a model of oxygen-glucose deprivation/reoxygenation (OGD/R). We observed pathological morphology and mitochondrial structure. Neuronal apoptosis was evident. Cell activity, cell respiration, FGF21, YY1, and antioxidant capacity were evaluated. I/R or OGD/R significantly increased the expressions of AK005401and YY1 and decreased FGF21expression, which further attenuated the activation of PI3K/Akt, promoted reactive oxygen species (ROS) generation, and then caused mitochondria dysfunction and cell apoptosis, which were reversed by AK005401 siRNA oligos and were aggravated by overexpression of AK005401 and YY1. We conclude that AK005401/YY1/FGF21 signaling pathway has an important role in I/R-mediated hippocampal injury.

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: A novel therapeutic target for diabetic nephropathy orchestrated renal fibrosis

BackgroundRenal fibrosis promotes the development of diabetic nephropathy (DN). A growing number of studies have reported that Yin Yang 1 (YY1), which is involved in cellular proliferation and differentiation, plays a crucial role in the pathogenesis of many diseases, such as pulmonary fibrosis, hepatic steatosis and cancer. MethodsWe detected the expression of YY1 under various glucose concentration and time gradient conditions. Rapamycin was used to verify the mTORC1/p70S6K/YY1 signaling pathway in HK-2 cells. We used db/db mice to examine the connection between renal fibrosis and YY1. A luciferase assay and chromatin immunoprecipitation (ChIP) assay were used to identify whether YY1 directly regulated α-SMA by binding to the α-SMA promoter. RNA silencing and overexpression were performed by using a YY1 expression/knockdown plasmid to investigate the function of YY1 in renal fibrosis of DN. ResultsYY1 expression and subsequent nuclear translocation were upregulated in a glucose- and time-dependent manner via the mTORC1/p70S6K signaling pathway in HK-2 cells. YY1 expression and nuclear translocation was significantly upregulated in db/db mice. Furthermore, YY1 upregulated α-SMA expression and activity in high-glucose-cultured HK-2 cells. Overexpression of YY1 promoted renal fibrosis in db/m mice mainly by upregulating α-SMA expression and inducing epithelial-mesenchymal transition (EMT) in vitro and in vivo. Finally, downregulation of YY1 reversed renal fibrosis by improving EMT in vivo and in vitro. ConclusionsThese results reveal that upregulation of YY1 plays a critical role in HG-induced deregulation of EMT-associated protein expression, which finally results in renal fibrosis of DN. Therefore, decreasing YY1 expression might represent a new therapeutic target for diabetic nephropathy-induced renal fibrosis.

Zinc-finger protein YY1 suppresses tumor growth of human nasopharyngeal carcinoma by inactivating c-Myc–mediated microRNA-141 transcription

Yin Yang 1 (YY1) is a zinc-finger protein that plays critical roles in various biological processes by interacting with DNA and numerous protein partners. YY1 has been reported to play dual biological functions as either an oncogene or tumor suppressor in the development and progression of multiple cancers, but its role in human nasopharyngeal carcinoma (NPC) has not yet been revealed. In this study, we found that YY1 overexpression significantly inhibits cell proliferation and cell-cycle progression from G1 to S and promotes apoptosis in NPC cells. Moreover, we identified YY1 as a component of the c-Myc complex and observed that ectopic expression of YY1 inhibits c-Myc transcriptional activity, as well as the promoter activity and expression of the c-Myc target gene microRNA-141 (miR-141). Furthermore, restoring miR-141 expression could at least partially reverse the inhibitory effect of YY1 on cell proliferation and tumor growth and on the expression of some critical c-Myc targets, such as PTEN/AKT pathway components both in vitro and in vivo We also found that YY1 expression is reduced in NPC tissues, negatively correlates with miR-141 expression and clinical stages in NPC patients, and positively correlates with survival prognosis. Our results reveal a previously unappreciated mechanism in which the YY1/c-Myc/miR-141 axis plays a critical role in NPC progression and may provide some potential and valuable targets for the diagnosis and treatment of NPC.

Regulation of Krüppel-Like Factor 4 (KLF4) expression through the transcription factor Yin-Yang 1 (YY1) in non-Hodgkin B-cell lymphoma.

Krüppel-Like Factor 4 (KLF4) is a member of the KLF transcription factor family, and evidence suggests that KLF4 is either an oncogene or a tumor suppressor. The regulatory mechanism underlying KLF4 expression in cancer, and specifically in lymphoma, is still not understood. Bioinformatics analysis revealed two YY1 putative binding sites in the KLF4 promoter region (-950 bp and -105 bp). Here, the potential regulation of KLF4 by YY1 in NHL was analyzed. Mutation of the putative YY1 binding sites in a previously reported system containing the KLF4 promoter region and CHIP analysis confirmed that these binding sites are important for KLF4 regulation. B-NHL cell lines showed that both KLF4 and YY1 are co-expressed, and transfection with siRNA-YY1 resulted in significant inhibition of KLF4. The clinical implications of YY1 in the transcriptional regulation of KLF4 were investigated by IHC in a TMA with 43 samples of subtypes DLBCL and FL, and all tumor tissues expressing YY1 demonstrated a correlation with KLF4 expression, which was consistent with bioinformatics analyses in several databases. Our findings demonstrated that KLF4 can be transcriptionally regulated by YY1 in B-NHL, and a correlation between YY1 expression and KLF4 was found in clinical samples. Hence, both YY1 and KLF4 may be possible therapeutic biomarkers of NHL.

MiR-141-3p Suppresses Tumor Growth and Metastasis in Papillary Thyroid Cancer via Targeting Yin Yang 1.

MicroR-141-3p has been found to be downregulated in papillary thyroid carcinoma (PTC), while little is known about the cellular functions and precise signals elicited by miR-141-3p in PTC. The results of this study indicated that the expression of miR-141-3p was aberrantly down-regulated in PTC tissues and cell lines, compared with the adjacent normal tissues and normal thyroid epithelial cells. Furthermore, the miR-141-3p expression level was negatively associated with TNM stage and lymph node metastasis in PTC. Expression of miR-141-3p effectively inhibited cell growth, promoted apoptosis, and suppressed invasion in PTC cells. Meanwhile, miR-141-3p knockdown with miR-141-3p inhibitor reversed these effects. Consistent with the in vitro study, miR-141-3p also exhibited anti-neoplastic activity in vivo. Moreover, the results revealed that miR-141-3p directly recognized the 3' untranslated region (3'UTR) of Yin Yang 1 (YY1) and negatively regulated the expression of YY1 at both protein and mRNA levels. Ectopic expression of YY1 could effectively abrogate the anti-metastatic and proapoptotic effects of miR-141-3p. In summary, the findings suggested that miR-141-3p can act as a tumor suppressor in PTC and may be a potential therapeutic target for PTC treatment. Anat Rec, 302:258-268, 2019. © 2018 Wiley Periodicals, Inc.

MiR-186 reverses cisplatin resistance and inhibits the�formation of the glioblastoma-initiating cell�phenotype by degrading Yin Yang 1 in glioblastoma

Glioblastoma multiforme (GBM) is among the most devastating types of cancer, with a median survival of <1year. Despite the development of new surgical and radiation techniques, and the use of multiple anti‑neoplastic drugs, effective treatment strategies for malignant gliomas have not yet been developed. The limited efficacy of current treatments reflects the resistance of glioblastoma cells to cytotoxic agents. In this study, using western blot analysis, we found that YinYang1(YY1) expression was increased in cisplatin‑resistant glioblastoma U87MG cells (U87MG‑CR). We observed that the silencing of YY1 sensitized the U87MG‑CR cells to cisplatin and that the overexpression of YY1 promoted the resistance of LN‑229 glioblastoma cells to cisplatin, as shown by MTT assay. Using sphere formation assay, we also found that the silencing of YY1 inhibited the formation of the glioblastoma‑initiating cell (GIC) phenotype in the U87MG‑CR cells. In addition, the results of RT‑qPCR revealed that miR‑186 expression was decreased in U87MG‑CR cells. Using RT‑PCR and western blot analysis, we observed that overexpression of miR‑186 inhibited YY1 expression in U87MG‑CR cells. The overexpression of miR‑186 also reversed cisplatin resistance and the formation of the GIC phenotype in glioblastoma cells. On the whole, the findings of this study demonstrate that miR‑186 reverses cisplatin resistance and inhibits the formation of the GIC phenotype by degrading YY1 in glioblastoma.

Blocking of YY1 reduce neutrophil infiltration by inhibiting IL-8 production via the PI3K-Akt-mTOR signaling pathway in rheumatoid arthritis

Our previous study revealed that Yin Yang 1(YY1) played an important part in promoting interleukin (IL)-6 production in rheumatoid arthritis (RA). However, whether YY1 has any role in regulation of IL-8 in RA remains unclear. YY1 and IL-8 expression in RA patients were analyzed by real-time polymerase chain reaction (PCR). Ingenuity pathway analysis (IPA) was used to analyze the signaling pathway involved in YY1-induced IL-8 production. The expression of YY1 and proteins involved in the pathway were detected by Western blot and enzyme-linked immunosorbent assay (ELISA). Migration of neutrophils was performed by chemotaxis assay. In this study, we found that high expression of IL-8 was positively associated with YY1 expression in RA. Blocking YY1 expression by YY1-short hairpin (sh)RNA lentivirus reduced IL-8 production. Mechanistically, we showed YY1 activated IL-8 production via the phosphatidylinositol-3-kinase/Akt/mammalian target of rapamycin (PI3K/Akt/mTOR) signaling pathway. Further, using a co-culture system consisting of peripheral blood mononuclear cells (PBMC) and neutrophils, we found that migration of neutrophils would be inhibited by YY1 RNA interference. Finally, using the collagen-induced arthritis animal model, we showed that treatment with the YY1-shRNA lentivirus led to reduction of IL-8 levels and attenuation of inflammation and neutrophil infiltration in vivo. Our results reveal a role of YY1 involved in neutrophil infiltration in RA via the PI3K/Akt/mTOR/IL-8 signaling pathway. YY1 may be a new therapeutic target for treatment of RA.

Hepatic expression of Yin Yang 1 (YY1) is associated with the non-alcoholic fatty liver disease (NAFLD) progression in patients undergoing bariatric surgery

BackgroundThis study is to investigate the association between the hepatic expression of Yin Yang 1 (YY1) and the progression of non-alcoholic fatty liver disease (NAFLD) in patients undergoing bariatric surgery.MethodsObese patients undergoing bariatric surgery were included. Liver tissues were subjected to the quantitative real-time PCR, Western blot analysis, and immunohistochemical assay, to determine the expression levels of YY1.ResultsTotally 88 patients were included. According to the NAFLD activity score (NAS), these patients were divided into the control (n = 12), steatosis (n = 20), non-defining NASH (n = 38), and NASH (n = 18) groups. Significant differences in the serum glucose, insulin, ALT, AST, and HOMA-IR levels were observed among these different NAFLD groups. Hepatic YY1 expression had correlation with serum glucose, insulin, HOMA-IR, ALT, AST, triglycerides, HDL, and GGT. Immunohistochemical analysis showed that, compared with the control group, the expression levels of YY1 were significantly higher in the non-defining NASH and NASH groups. In addition, multivariate regression model showed that the serum ALT and YY1 levels were strongly associated with the NAFLD activity.ConclusionsSeveral factors are associated with NAFLD progression, including the expression of YY1. Our findings contribute to understanding of the pathogenesis of NAFLD.Trial registrationNCT03296605, registered on September 28, 2017.

Oxidative stress-elicited YY1 potentiates antioxidative response via enhancement of NRF2-driven transcriptional activity: A potential neuronal defensive mechanism against ischemia/reperfusion cerebral injury.

Cerebral ischemia challenge evokes an adaptive defensive system through the induction of antioxidant enzymes. Many of such antioxidant enzymes are regulated essentially by the nuclear factor erythroid 2-related factor-2 (NRF2). Compelling evidence supports that targeting NRF2 signaling is a promising therapeutic strategy to alleviate post-I/R brain injury, but the molecular mechanisms underlying this strategy have yet to be elucidated. Herein, we show that the expression of transcription factor Yin Yang 1 (YY1) is significantly upregulated during the recovery following middle cerebral artery occlusion (MCAO). Ablation of endogenous YY1 using cerebral ventricle injection of siRNA exacerbated I/R-induced neuronal damage and attenuated the antioxidant defensive system. Mechanistically, low levels of reactive oxygen species (ROS) production stimulated neuronal YY1 expression, whereas high levels of ROS exhibited a noticeable inhibitory effect. The evoked YY1, in concert with other coregulators, recruited to the antioxidant responsive elements (AREs) binding site and then amplified the NRF2-mediated ARE transcription, thereby protecting cells against damage by potentiating antioxidant response. In this regard, compromise of YY1 expression by ROS overactivity is an important etiology that sabotages the antioxidant defensive system and consequently deteriorate s neuronal damage following I/R injury. Taken together, our findings provide novel evidence on a delicate and synergistical collaboration between YY1 and the master transcription factor NRF2 that functions to mobilize the cell's antioxidant machinery.

MiR-147b influences vascular smooth muscle cell proliferation and migration via targeting YY1 and modulating Wnt/β-catenin activities.

Cardiovascular disease is the leading cause of death worldwide. Dysregulation of microRNAs (miRNAs) has been found to be associated with cardiovascular diseases such as atherosclerosis. In the present study, we examined the role of miR-147b in the proliferation and migration of vascular smooth muscle cells (VSMCs). Quantitative real-time PCR was performed to determine the expression levels of miR-147b and Yin Yang 1 (YY1) mRNA. CCK-8, transwell migration and wound healing assays were used to determine cell proliferation and migration of VSMCs, respectively. Luciferase reporter assay confirmed the downstream target of miR-147b. The protein level of YY1 was measured by western blot analysis. Platelet-derived growth factor-bb (PDGF-bb) treatment promoted cell proliferation and increased miR-147b expression in VSMCs. Overexpression of miR-147b enhanced cell proliferation and migration of VSMCs, while knock-down of miR-147b suppressed cell proliferation and migration of VSMCs or PDGF-bb-treated VSMCs. Further, bioinformatics prediction and luciferase reporter assay showed that YY1 was a downstream target of miR-147b, and miR-147b negatively regulated the mRNA and protein expression of YY1 in VSMCs. Overexpression of YY1 inhibited cell proliferation and migration of VSMCs and attenuated the effects of miR-147b overexpression on cell proliferation and migration. In addition, overexpression of miR-147b increased the Wnt/β-catenin signaling activities in VSMCs. In conclusion, our results suggest that miR-147b plays important roles in the control of cell proliferation and migration of VSMCs possibly via targeting YY1.

YinYang1 deficiency ameliorates joint inflammation in a murine model of rheumatoid arthritis by modulating Th17 cell activation

Yin Yang 1 (YY1) is a ubiquitously expressed transcription factor that functions in cooperation with various cofactors to regulate gene expression. In the immune system, YY1 enhances cytokine production and T helper (Th) 2 effector cell differentiation, resulting in the activation of inflammation. However, no studies have reported the role of YY1 in Th17 cell regulation, which is implicated in rheumatoid arthritis (RA). We investigated the expression of YY1 in Th17 cells in vitro and revealed increased levels of YY1 mRNA and protein. To elucidate the function of YY1 pathogenesis in RA, we used a collagen-induced arthritis (CIA) mouse model with YY1 deficiency. Deficiency of YY1 reduced the severity of arthritis and joint destruction. Moreover, Th17 cells were dramatically reduced in YY1-deficient mice. The cytokine interleukin (IL)-17 was decreased in YY1-deficient CD4+ T cells ex vivo and in vivo. Interestingly, the level of signal transducer and activator of transcription 3 (STAT3), tumor necrosis factor-α, IL-17, IL-6, and IL-1β were markedly decreased in YY1-deficient mice with CIA. The cytokine-inducing function of YY1 was more specific to IL-17 than to interferon-γ. YY1 plays a role in Th17 cell differentiation and RA pathogenesis. Our findings suggest that future RA therapies should target the regulatory mechanism involved in Th17 cell differentiation, in which YY1 may cooperate with the STAT3 signaling pathway.

YY1 Positively Regulates Transcription by Targeting Promoters and Super-Enhancers through the BAF Complex in Embryonic Stem Cells.

SummaryYin Yang 1 (YY1) regulates early embryogenesis and adult tissue formation. However, the role of YY1 in stem cell regulation remains unclear. YY1 has a Polycomb group (PcG) protein-dependent role in mammalian cells. The PcG-independent functions of YY1 are also reported, although their underlying mechanism is still undefined. This paper reports the role of YY1 and BAF complex in the OCT4-mediated pluripotency network in mouse embryonic stem cells (mESCs). The interaction between YY1 and BAF complex promotes mESC proliferation and pluripotency. Knockdown of Yy1 or Smarca4, the core component of the BAF complex, downregulates pluripotency markers and upregulates several differentiation markers. Moreover, YY1 enriches at both promoter and super-enhancer regions to stimulate transcription. Thus, this study elucidates the role of YY1 in regulating pluripotency through its interaction with OCT4 and the BAF complex and the role of BAF complex in integrating YY1 into the core pluripotency network.

Expression of Yin Yang 1 in cervical cancer and its correlation with E-cadherin expression and HPV16 E6.

The molecular mechanisms of normal cervical squamous epithelium advancing to cervical intraepithelial neoplasia (CIN) and eventually to cervical squamous cell carcinoma (CSCC) are largely unknown. This study explored abnormal expression of Yin Yang 1 (YY1) in cervical cancer and its correlation with the expression of E-cadherin and human papillomavirus (HPV) 16 E6. YY1, E-cadherin and HPV16 E6 expression were detected by immunohistochemistry in 90 cervical tissue specimens collected from 30 patients with hysteromyoma, 15 patients with CIN I, 15 patients with CIN II-III, and 30 patients with CSCC. The H-score method was employed to measure the expression of YY1, E-cadherin and HPV16 E6. Increased expression of YY1 and HPV16 E6, and the decreased expression levels of E-cadherin were strongly associated with malignant transformation of the cervical epithelium and the histological progression of CSCC. The expression of YY1 in cervical tissues was inversely correlated with E-cadherin expression, and positively correlated with HPV16 E6 expression. Expression of YY1 in CSCC tissues was not significantly correlated with tumor differentiation, but was significantly correlated with an advanced clinical stage of CSCC. These results suggest that up-regulation of YY1 is closely associated with the progression of CSCC, and YY1 may play an important role in the pathogenesis of cervical cancer by modulating the expression of E-cadherin and HPV16 E6.

The Yin and Yang of YY1 in tumor growth and suppression.

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.

Multifunctional YY1 in Liver Diseases.

The transcription factor Yin Yang 1 (YY1) is a multifunctional protein that can activate or repress gene expression, depending on the cellular context. While YY1 is ubiquitously expressed and highly conserved between species, its role varies among the diverse cell types and includes proliferation, differentiation, and apoptosis. Upregulated YY1 expression is found in pathogenic conditions, such as human hepatocellular carcinoma and hepatitis B virus infection, and its roles in the molecular pathogenic mechanisms in liver (i.e., fibrosis, carcinogenesis, viral-induced injury) are currently being elucidated. The most recent studies have revealed that YY1 is deeply involved in such dysregulated cellular metabolisms as glycometabolism, lipid metabolism, and bile acid metabolism, which are all involved in various diseases. In this review, we will summarize the current knowledge on YY1 in liver diseases, providing a focused discussion on the characterized and probable underlying mechanisms, as well as a reasoned evaluation of the potential for YY1-mediated pathology as drug targets in liver disease therapies.

Transcription Factor YY1 Modulates Lung Cancer Progression by Activating lncRNA-PVT1.

Lung cancer is the leading cause of cancer-related death worldwide. Despite the advancement in surgery and chemotherapy, the prognosis of patients with advanced lung cancer is still poor. Yin Yang-1 (YY1) is a multifunctional transcription factor that exhibits positive and negative control on a large number of cellular and viral genes. In this study, we showed that the expression of YY1 is upregulated in lung cancer tissues as compared to adjacent normal tissues. Patients with higher expression of YY1 had larger tumor size, poor differentiation, higher TNM stage, and lymph node metastasis. Ectopic expression of YY1 in lung cancer cells promoted cell proliferation and invasion. Inversely, siRNA-mediated silencing of YY1 inhibited cell proliferation and induced apoptosis. These results suggested that YY1 may function as an oncogene in lung cancer. Moreover, through luciferase reporter assay, electrophoretic mobility shift assay, and chromatin immunoprecipitation assay, we showed that YY1 could directly bind to the promoter region of (long noncoding RNA-plasmacytoma variant translocation 1 [lncRNA-PVT1]) and activated its transcription through the consensus YY1 motif. Knockdown of the expression of YY1 reduced cell proliferation in vivo, consistent with the results obtained from silencing the expression of YY1 in lung cancer cells. Collectively, our study showed a critical role of YY1 in the regulation of tumorigenesis, partly through its downstream target PVT1.

Yin Yang-1 suppresses pancreatic ductal adenocarcinoma cell proliferation and tumor growth by regulating SOX2OT-SOX2 axis

The transcription regulator Yin Yang-1 (YY1) serves as a tumor suppressor in pancreatic ductal adenocarcinoma (PDAC). However, the function of YY1 in proliferation of PDAC cells remains to be clarified. In this study, we found that overexpression of YY1 suppressed proliferation and decreased the expression of long non-coding RNA (lncRNA) SOX2OT and its potential target gene SOX2 in PDAC cells. Luciferase reporter, electrophoretic mobility shift (EMSA), and chromatin immunoprecipitation (ChIP) assays revealed binding of YY1 to the SOX2OT promoter. Moreover, YY1 suppressed PDAC cell proliferation through SOX2OT transcriptional inhibition and subsequent decreased SOX2 expression. In addition, YY1 expression was statistically negatively correlated with SOX2OT and SOX2 expression in PDAC tissues and lower level expression of SOX2OT predicted better outcome in PDAC patients. These results confirmed the anti-proliferation effect of YY1 on PDAC cells, which was associated with SOX2 down-regulation in a SOX2OT-dependent mechanism. Although other undiscovered mechanisms may be involved in the YY1-mediated tumor suppression role, the present study suggests that SOX2OT may act as a tumor promotor in PDAC and may represent a valuable diagnostic and therapeutic target.