Yin Yang 1 Levels Research Articles

NRIP1 is a downstream target of YY1 in promoting OGD/R-induced H9c2 cardiomyocyte injury and mitochondrial dysfunction.

From a clinical standpoint, myocardial ischemia/reperfusion injury (MIRI) has always been an enormous challenge for the treatment of acute myocardial infarction (AMI). Molecular targeting therapy may help overcome this challenge. The present work aimed to elucidate the possible involvement of Yin-Yang 1 (YY1)/nuclear receptor-interacting protein 1 (NRIP1) and discover the molecular mechanism of MIRI. Herein, a cardiomyocyte ischemia/reperfusion (I/R) model was established via oxygen-glucose deprivation/re-oxygenation (OGD/R) damage in H9c2 cardiomyocytes. Reverse transcription-quantitative PCR and western blotting were conducted to measure the levels of YY1 and NRIP1 at the RNA and protein levels, respectively. H9c2 cell viability and apoptosis were assayed using the Cell Counting Kit-8, flow cytometry, and western blotting. In addition, superoxide dismutase, glutathione peroxidase, and malondialdehyde levels were analyzed as markers of oxidative stress. Additionally, mitochondrial membrane potential, which was measured via JC-1 staining, ATP content, Complex I activity, mitochondrial DNA copy number, and mitochondrial permeability transition pore (mPTP) opening rate were analyzed to evaluate mitochondrial activity. Moreover, luciferase reporter and chromatin immunoprecipitation assays experimentally validated the predicted affinity of YY1 with the NRIP1 promoter according to the HumanTFDB online tool. YY1/NRIP1 were both highly expressed in OGD/R-injured H9c2 cardiomyocytes. Downregulation of NRIP1 improved cell viability, whereas it inhibited cell apoptosis and oxidative stress, and suppressed mitochondrial dysfunction in OGD/R-injured H9c2 cardiomyocytes. Importantly, it was verified that YY1 could bind to the NRIP1 promoter to positively regulate NRIP1 expression. The protective effects of NRIP1 knockdown against cardiomyocyte damage and mitochondrial dysfunction in OGD/R-injured H9c2 cardiomyocytes were partly abolished through overexpression of YY1. NRIP1 emerged as a downstream target of YY1 in promoting OGD/R-induced H9c2 cardiomyocyte injury and mitochondrial dysfunction, providing novel ideas for targeted treatments to alleviate MIRI.

RNA polymerase I subunit D activated by Yin Yang 1 transcription promote cell proliferation and angiogenesis of colorectal cancer cells.

This study aims to explore possible effect of RNA polymerase I subunit D (POLR1D) on proliferation and angiogenesis ability of colorectal cancer (CRC) cells and mechanism herein. The correlation of POLR1D and Yin Yang 1 (YY1) expressions with prognosis of CRC patients in TCGA database was analyzed. Quantitative realtime polymerase chain reaction (qRT-PCR) and Western blot were applied to detect expression levels of POLR1D and YY1 in CRC cell lines and CRC tissues. SW480 and HT- 29 cells were transfected with si-POLR1D or pcDNA3.1-POLR1D to achieve POLR1D suppression or overexpression before cell migration, angiogenesis of human umbilical vein endothelial cells were assessed. Western blot was used to detect expressions of p38 MAPK signal pathway related proteins and interaction of YY1 with POLR1D was confirmed by dual luciferase reporter gene assay and chromatin immunoprecipitation (ChIP). TCGA data showed that both POLR1D and YY1 expressions were up-regulated in CRC patients. High expression of POLR1D was associated with poor prognosis of CRC patients. The results showed that POLR1D and YY1 were highly expressed in CRC cell lines. Inhibition or overexpression of POLR1D can respectively suppress or enhance proliferation and angiogenesis of CRC cells. YY1 inhibition can suppress CRC progression and deactivate p38 MAPK signal pathway, which can be counteracted by POLR1D overexpression. JASPAR predicted YY1 can bind with POLR1D promoter, which was confirmed by dual luciferase reporter gene assay and ChIP. YY1 transcription can up-regulate POLR1D expression to activate p38 MAPK signal pathway, thus promoting proliferation and angiogenesis ability of CRC cells.

A mutual regulatory loop between transcription factor Yin Yang 1 and hepatitis B virus replication influences chronic hepatitis B

Hepatitis B virus (HBV) infections pose a major threat to human health. HBV can upregulate the expression of the transcription factor Yin Yang 1 (YY1) in in vitro cytological experiments, suggesting an association between YY1 and HBV infection. However, data on YY1 expression in chronic hepatitis B (CHB) patients are lacking. In this study, we aimed to assess the correlation between YY1 expression and HBV infection. We detected serum YY1 levels in 420 patients with chronic HBV infection, 30 patients with chronic hepatitis C virus infection, and 32 healthy controls using an enzyme-linked immunosorbent assay. The correlation between YY1 levels and clinical parameters was analyzed. Meanwhile, the changes of YY1 before and after interferon or entecavir treatment were analyzed. YY1 levels in the liver tissues were detected using immunofluorescence staining. The expression of YY1 in HBV-expressing cells was detected through western blotting. Meanwhile, we explored the effects of YY1 on HBV replication and gene expression. We found that YY1 was highly expressed in the serum and liver tissues of CHB patients. Serum YY1 levels positively correlated with HBV DNA and hepatitis B surface antigen (HBsAg). Additionally, HBV DNA levels increased but HBsAg levels decreased after HBV-expressing cells overexpress YY1. In conclusion, our study demonstrates that YY1 plays an important role in HBV replication and gene expression, providing a potential target for the treatment of CHB.

The DDX6/KIFC1 signaling axis, as regulated by YY1, contributes to the malignant behavior of pancreatic cancer.

Human DEAD/H box RNA helicase DDX6 acts as an oncogene in several different types of cancer, where it participates in RNA processing. Nevertheless, the role of DDX6 in pancreatic cancer (PC), together with the underlying mechanism, has yet to be fully elucidated. In the present study, compared with adjacent tissues, the level of DDX6 was abnormally increased in human PC tissues, and this increased level of expression was associated with poor prognosis. Furthermore, the role of DDX6 in PC was investigated by overexpressing or silencing the DDX6 in the PC cell lines, SW1990 and PaTu-8988t. A xenograft model was established by injecting nude mice with either DDX6-overexpressing or DDX6-silenced SW1990 cells. DDX6 overexpression promoted the proliferation and cell cycle transition, inhibited the cell apoptosis of PC cells, and accelerated tumor formation, whereas DDX6 knockdown elicited the opposite effects. DDX6 exerted positive effects on PC. RNA immunoprecipitation assay showed that DDX6 bound to kinesin family member C1 (KIFC1) mRNA, which was further confirmed by RNA pull-down assay. These results suggested that DDX6 positively regulated the expression of KIFC1. KIFC1 overexpression enhanced the proliferative capability of PC cells with DDX6 knockdown and inhibited their apoptosis. By contrast, DDX6 overexpression reversed the inhibitory effect of KIFC1 silencing on tumor proliferation. Subsequently, the transcription factor Yin Yang 1 (YY1) was shown to negatively regulate DDX6 at both the mRNA and protein levels. Dual-luciferase reporter assay verified that YY1 targeted the promoter of DDX6 and inhibited its transcription. High expression levels of YY1 decreased the proliferation of PC cells and promoted cell apoptosis, although these effects were reversed by DDX6 overexpression. Taken together, YY1 may target the DDX6/KIFC1 axis, thereby negatively regulating its expression, leading to an inhibitory effect on pancreatic tumor.

Brucine alleviates fibroblast-like synoviocytes dysfunction and inflammation by regulating YY1 during rheumatoid arthritis.

Brucine is a weak alkaline indole alkaloid with wide pharmacological activities and has been identified to protect against rheumatoid arthritis (RA) process. Circular RNAs (circRNAs) are also reported to be involved in the pathogenesis of RA. Here, we aimed to probe the role and mechanism of Brucine and circ_0139658 in RA progression. The fibroblast-like synoviocytes of RA (RA-FLSs) were isolated for functional analysis. Cell proliferation, apoptosis, invasion, migration, as well as inflammatory response were evaluated by CCK-8 assay, EdU assay, flow cytometry, transwell assay, and ELISA analysis, respectively. qRT-PCR and western blotting analyses were utilized to measure the levels of genes and proteins. The binding between miR-653-5p and circ_0139658 or Yin Yang 1 (YY1), was verified using dual-luciferase reporter and RNA pull-down assays. Brucine suppressed the proliferation, migration, and invasion of RA-FLSs, and alleviated inflammation by reducing the release of pro-inflammatory factors and macrophage M1 polarization. RA-FLSs showed increased circ_0139658 and YY1 levels and decreased miR-653-5p levels. Circ_0139658 is directly bound to miR-653-5p to regulate YY1 expression. Brucine treatment suppressed circ_0139658 and YY1 expression but increased YY1 expression in RA-FLSs. Functionally, circ_0139658 overexpression reversed the suppressing effects of Brucine on RA-FLS dysfunction and inflammation. Moreover, circ_0139658 silencing alleviated the dysfunction and inflammation in RA-FLSs, which were reverted by YY1 overexpression. Brucine suppressed the proliferation, migration, invasion, and inflammation in RA-FLSs by decreasing YY1 via circ_0139658/miR-653-5p axis.

Yin Yang 1 facilitates the activation, inflammation, and extracellular matrix deposition of hepatic stellate cells in hepatic fibrosis.

Chronic hepatic diseases often involve fibrosis as a pivotal factor in their progression. This study investigates the regulatory mechanisms of Yin Yang 1 (YY1) in hepatic fibrosis. Our data reveal that YY1 binds to the prolyl hydroxylase domain 1 (PHD1) promoter. Rats treated with carbon tetrachloride (CCl4) display heightened fibrosis in liver tissues, accompanied by increased levels of YY1, PHD1, and the fibrosis marker alpha-smooth muscle actin (α-SMA). Elevated levels of YY1, PHD1, and α-SMA are observed in the liver tissues of CCl4-treated rats, primary hepatic stellate cells (HSCs) isolated from fibrotic liver tissues, and transforming growth factor beta-1 (TGF-β1)-induced HSCs. The human HSC cell line LX-2, upon YY1 overexpression, exhibits enhanced TGF-β1-induced activation, leading to increased expression of extracellular matrix (ECM)-related proteins and inflammatory cytokines. YY1 silencing produces the opposite effect. YY1 exerts a positive regulatory effect on the activation of the phosphatidylinositol 3-kinase (PI3K)/protein kinase B (AKT) signaling pathway and PHD1 expression. PHD1 silencing rescues the promotion of YY1 in cell activation, ECM-related protein expression, and inflammatory cytokine production in TGF-β1-treated LX-2 cells. Overall, our findings propose a model wherein YY1 facilitates TGF-β1-induced HSC activation, ECM-related protein expression, and inflammatory cytokine production by promoting PHD1 expression and activating the PI3K/AKT signaling pathway. This study positions YY1 as a promising therapeutic target for hepatic fibrosis.

Regulation of TREM2 expression by transcription factor YY1 and its protective effect against Alzheimer’s disease

TREM2 encoding the transmembrane receptor protein TREM2 is a risk gene of Alzheimer's disease (AD), and the impairment of TREM2 functions in microglia due to mutations in TREM2 may significantly increase the risk of AD by promoting AD pathologies. However, how the expression of TREM2 is regulated and the transcription factors required for TREM2 expression are largely unknown. By luciferase assay, DNA pull-down, and in silico predictions, we identified Yin Yang 1(YY1) as a binding protein of the minimal promoter of the TREM2 gene, and the binding was further confirmed by EMSA and DNA pull-down assay. shRNA-mediated YY1 silencing significantly reduced the activity of the TREM2 minimal promoter and TREM2 protein levels in the microglial cell line BV2 and the neuroblastoma Neuro2A. Furthermore, we found that the levels of TREM2 and YY1 were both downregulated in lipopolysaccharide-treated BV2 cells and in the brain of AD model mice. These results demonstrated that YY1 plays a crucial role in the regulation of TREM2 expression. Our study suggests that microglial YY1 could be targeted to maintain TREM2 expression for AD prevention and therapy.

Hsa_circ_0001925 promotes malignant progression in triple-negative breast cancer via miR-1299/YY1 axis.

Circular RNAs (circRNAs) are related to the pathogenesis and progression of triple-negative breast cancer (TNBC). The aim of this study was to investigate the role and mechanism of hsa_circ_0001925 in TNBC progression. Hsa_circ_0001925, microRNA (miR)-1299 and Yin Yang 1 (YY1) levels were examined in TNBC via reverse transcription-quantitative polymerase chain reaction (RT-qPCR) and western blot. Cell counting kit-8 (CCK-8), colony formation, 5-ethynyl-2'-deoxyuridine (EdU) staining, flow cytometry, wound healing assay and tube formation assay were conducted to estimate the effects of hsa_circ_0001925 on malignant phenotypes of TNBC tumors. Several protein levels were measured with western blot. The regulatory relationship between miR-1299 and hsa_circ_0001925 or YY1 was validated using a dual-luciferase reporter and RNA immunoprecipitation (RIP) assays. Xenograft assay was used to estimate the effect of hsa_circ_0001925 in TNBC in vivo. Hsa_circ_0001925 and YY1 levels were upregulated, while miR-1299 abundance was downregulated in TNBC tissues and cells. Hsa_circ_0001925 silencing constrained cell proliferation, migration and angiogenesis whereas it promoted apoptosis in vitro, and hsa_circ_0001925 silencing significantly curbed xenograft tumor growth in vivo. Hsa_circ_0001925 acted as a miRNA sponge for miR-1299. Hsa_circ_0001925 decreased YY1 expression by sponging miR-1299. MiR-1299 downregulation alleviated the effects of hsa_circ_0001925 knockdown on BC progression. MiR-1299 interacted with the 3' untranslated region (3' UTR) of YY1, and YY1 overexpression partly reversed the effects of miR-1299 overexpression on BC progression. Our findings showed that hsa_circ_0001925 mediated TNBC progression via regulating miR-1299/YY1 axis, providing a potential target for BC treatment.

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.

YY1 (Yin-Yang 1), a transcription factor regulating systemic inflammation, is involved in cognitive impairment of depression.

Clinical and preclinical studies suggest that alterations in the peripheral and brain immune system are associated with the pathophysiology of depression, also leading to changes in local glucose metabolism in the brain. Here, the authors identified Yin-Yang 1 (YY1), a transcription factor closely associated with central and peripheral inflammation. Plasma levels of YY1, interleukin (IL) 6, and IL-1β in major depressive disorder (MDD) were collected before and after treatment with vortioxetine, and correlation with clinical and cognitive scores was studied. Chronic unpredictable mild stress was treated with vortioxetine. Micropositron emission tomography (microPET) was used to analyze glucose metabolism and mRNA, and the protein level of the YY1-nuclear factor κB (NF-κB)-IL-1β inflammatory pathway were measured in related brain regions. Plasma levels of YY1 and IL-1β were significantly increased in MDD and decreased after treatment with vortioxetine. Meanwhile, the level of YY1 in plasma was negatively correlated with cognitive functions in patients with MDD and positively correlated with the level of IL-1β in plasma. Compared with the control group, in chronic unpredictable mild stress rats, (microPET)analysisshowed that the decrease of glucose metabolism in the hippocampus, entorhinal cortex, amygdala, striatum, and medial prefrontal cortex was reversed after treatment. mRNA and protein level of related molecular in YY1-NF-κB-IL-1β inflammatory pathway decreased in the hippocampus and was reversed by vortioxetine. The current study suggests that the YY1-NF-κB-IL-1β inflammatory pathway may play an essential role in both mood changes and cognitive impairment in depression, and may be associated with changes in glucose metabolism in emotion regulation and cognition. These findings provide new evidence for the inflammatory mechanisms of depression.

The Non-Specific Lethal (NSL) Histone Acetyltransferase Complex Transcriptionally Regulates Yin Yang 1-Mediated Cell Proliferation in Human Cells.

The human males absent on the first (MOF)-containing non-specific lethal (NSL) histone acetyltransferase (HAT) complex acetylates histone H4 at lysine K5, K8, and K16. This complex shares several subunits with other epigenetic regulatory enzymes, which highlights the complexity of its intracellular function. However, the effect of the NSL HAT complex on the genome and target genes in human cells is still unclear. By using a CRISPR/Cas9-mediated NSL3-knockout 293T cell line and chromatin immunoprecipitation-sequencing (ChIP-Seq) approaches, we identified more than 100 genes as NSL HAT transcriptional targets, including several transcription factors, such as Yin Yang 1 (YY1) which are mainly involved in cell proliferation, biological adhesion, and metabolic processes. We found here that the ChIP-Seq peaks of MOF and NSL3 co-localized with H4K16ac, H3K4me2, and H3K4me3 at the transcriptional start site of YY1. In addition, both the mRNA and protein expression levels of YY1 were regulated by silencing or overexpressing NSL HAT. Interestingly, the expression levels of cell division cycle 6, a downstream target gene of YY1, were regulated by MOF or NSL3. In addition, the suppressed clonogenic ability of HepG2 cells caused by siNSL3 was reversed by overexpressing YY1, suggesting the involvement of YY1 in NSL HAT functioning. Additionally, de novo motif analysis of MOF and NSL3 targets indicated that the NSL HAT complex may recognize the specific DNA-binding sites in the promoter region of target genes in order to regulate their transcription.

YY1 Silencing Induces 5-Fluorouracil-Resistance and BCL2L15 Downregulation in Colorectal Cancer Cells: Diagnostic and Prognostic Relevance.

Colorectal cancer (CRC) is characterized by genetic heterogeneity and is often diagnosed at an advanced stage. Therefore, there is a need to identify novel predictive markers. Yin Yang 1 (YY1) is a transcription factor playing a dual role in cancer. The present study aimed to investigate whether YY1 expression levels influence CRC cell response to therapy and to identify the transcriptional targets involved. The diagnostic and prognostic values of YY1 and the identified factor(s) in CRC patients were also explored. Silencing of YY1 increased the resistance to 5-Fluorouracil-induced cytotoxicity in two out of four CRC cells with different genotypes. BCL2L15/Bfk pro-apoptotic factor was found selectively expressed in the responder CRC cells and downregulated upon YY1 knockdown. CRC dataset analyses corroborated a tumor-suppressive role for both YY1 and BCL2L15 whose expressions were inversely correlated with aggressiveness. CRC single-cell sequencing dataset analyses demonstrated higher co-expression levels of both YY1 and BCL2L15 within defined tumor cell clusters. Finally, elevated levels of YY1 and BCL2L15 in CRC patients were associated with larger relapse-free survival. Given their observed anti-cancer role, we propose YY1 and BCL2L15 as candidate diagnostic and prognostic CRC biomarkers.

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

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 YY1 flox/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.

Long noncoding RNA LINC01578 drives colon cancer metastasis through a positive feedback loop with the NF-κB/YY1 axis.

Metastasis accounts for poor prognosis of cancers and related deaths. Accumulating evidence has shown that long noncoding RNAs (lncRNAs) play critical roles in several types of cancer. However, which lncRNAs contribute to metastasis of colon cancer is still largely unknown. In this study, we found that lncRNA LINC01578 was correlated with metastasis and poor prognosis of colon cancer. LINC01578 was upregulated in colon cancer, associated with metastasis, advanced clinical stages, poor overall survival, disease-specific survival, and disease-free survival. Gain-of-function and loss-of-function assays revealed that LINC01578 enhanced colon cancer cell viability and mobility invitro and colon cancer liver metastasis invivo. Mechanistically, nuclear factor kappa B (NF-κB) and Yin Yang 1 (YY1) directly bound to the LINC01578 promoter, enhanced its activity, and activated LINC01578 expression. LINC01578 was shown to be a chromatin-bound lncRNA, which directly bound NFKBIB promoter. Furthermore, LINC01578 interacted with and recruited EZH2 to NFKBIB promoter and further repressed NFKBIB expression, thereby activating NF-κB signaling. Through activation of NF-κB, LINC01578 further upregulated YY1 expression. Through activation of the NF-κB/YY1 axis, LINC01578 in turn enhanced its own promoter activity, suggesting that LINC01578 and NF-κB/YY1 formed a positive feedback loop. Blocking NF-κB signaling abolished the oncogenic roles of LINC01578 in colon cancer. Furthermore, the expression levels of LINC01578, NFKBIB, and YY1 were correlated in clinical tissues. Collectively, this study demonstrated that LINC01578 promoted colon cancer metastasis via forming a positive feedback loop with NF-κB/YY1 and suggested that LINC01578 represents a potential prognostic biomarker and therapeutic target for colon cancer metastasis.

Effects of miR-384 and miR-134-5p Acting on YY1 Signaling Transduction on Biological Function of Gastric Cancer Cells.

ObjectiveTo explore the related influencing mechanism of miR-384 and miR-134-5p acting on Yin Yang 1 (YY1) signaling transduction on the biological function of gastric cancer (GC) cells.MethodsmiR-384, miR-134-5p and YY1 levels in human GC cell lines KATO III, MKN-45, SNU-1 and normal gastric cell line GES-1 were measured by polymerase chain reaction (PCR). Dual luciferase reporter (DLR) gene assay and Western blot (WB) were employed for correlation analysis between miR-384, miR-134-5p and YY1. miR-384-inhibitor, miR-384-mimics, empty plasmid (miRNA-NC) and sh-YY1 were transfected into KATO III cells. Cell proliferation was determined by 3-(4,5-Dimethylthiazolyl-2)-2,5-Diphenyl Tetrazolium Bromide (MTT), cell invasion was measured by Transwell, and apoptosis was analyzed by flow cytometry (FC).ResultsIn KATO III, MKN-45 and SNU-1 cell lines, YY1 was upregulated while miR-384 and miR-134-5p were downregulated (P<0.001). The expression of miR-134-5p in the miR-134-5p-inhibitor group was significantly lower (P<0.001), while that in the miR-134-5p-mimics group was significantly higher (P<0.001). The expression of miR-384 in the miR-384-inhibitor group was significantly lower (P<0.001), and that in the miR-384-mimics group was significantly higher as compared to the NC group (P<0.001). Both miR-384 and miR-134-5p overexpression could inhibit cell proliferation and invasion, and promote apoptosis. As detected by WB, overexpressed miR-384 and miR-134-5p inhibited the expression of EMT-related molecular markers. Compared with sh-YY1, the number of cells in S phase decreased, the pro-apoptotic proteins boosted statistically, and the anti-apoptotic proteins declined notably after transfecting miR-134-5p-mimics/sh-YY1 or miR-384-mimics/sh-YY1 (P<0.05). The tumor growth rate of nude mice in miR-134-5p/sh-YY1 and miR-384/sh-YY1 groups were significantly lower than those in sh-YY1 group (all P<0.001).ConclusionBy targeting YY1 signaling transduction, miR-134-5p and miR-384 can alter the growth and apoptosis of GC cells, which are promising targets for new therapeutics of GC.

YY1lo NKT cells are dedicated IL-10 producers

Co-expression of Yin Yang 1 (YY1) is required for the full function of the transcription factor, PLZF, which is essential for the development of natural killer T cell (NKT cell) effector functions. Discordant expression of YY1 and PLZF, therefore, might define NKT cell subsets with distinct effector functions. A subset of NKT cells was identified that expressed low levels of YY1. YY1lo NKT cells were found in all tissues, had a mature phenotype and, distinct from other NKT cells, expressed almost no ThPOK or Tbet. When activated, YY1lo NKT cells produced little IL-4 or IFN-γ. YY1lo NKT cells were found to constitutively transcribe IL-10 mRNA and, accordingly, produced IL-10 upon primary activation. Finally, we find that tumor infiltrating NKT cells are highly enriched for the YY1lo subset. Low YY1 expression, therefore, defines a previously unrecognized NKT cell subset that is committed to producing IL-10.

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.

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.

YY1 suppresses proliferation and migration of pancreatic ductal adenocarcinoma by regulating the CDKN3/MdM2/P53/P21 signaling pathway.

Pancreatic ductal adenocarcinoma (PDAC) is one of the malignant lethal tumors. It has been reported that the transcriptional regulator Yin Yang-1 (YY1) suppressed the invasion and metastasis of PDAC. However, the function of YY1 on proliferation and migration of pancreatic cancer remains to be clarified. In this study, we found that YY1 overexpression or knockdown can inhibit or promote the proliferation and migration of pancreatic cancer cells. Digital gene expression sequencing indicates that cyclin-dependent kinase inhibitor 3 (CDKN3) may be the candidate target gene of YY1. Then we found that YY1 can downregulate the expression of CDKN3 by directly binding to the promoter region of CDKN3. Silencing CDKN3 expression could inhibit the ability of cell proliferation and migration and overexpression of CDKN3 could restore the effects induced by YY1 overexpression in pancreatic cancer cells. The expression levels of YY1 and CDKN3 were negatively correlated in pancreatic cancer tissues and PDAC patients with higher levels of CDKN3 have poor prognosis. Vitro and vivo study show that CDKN3 can form a complex with MdM2-P53, thus leading to inhibiting the expression of P21, which is the target gene of P53, and finally facilitates the cell cycle to promote the proliferation of pancreatic cancer cells. Hence, YY1 can directly regulate the expression of CDKN3 and participate in the cycle of pancreatic cancer cells, which can inhibit the progression of pancreatic cancer. These results reveal that YY1-CDKN3-MDM2/P53-P21 axis is involved in pancreatic tumorigenesis, which may develop new methods for human pancreatic cancer therapy.

The Forgotten YY2 in Reported YY1 Expression Levels in Human Cancers.

The transcription factor Yin Yang 1 (YY1) has been reported to be overexpressed in the majority of human cancers and that overexpression has prognostic significance. YY1 regulates several properties associated with cancer cells, including cell survival, cell proliferation, endothelial-mesenchymal transition, metastases, and resistance to both chemotherapeutics and immunotherapeutics. Although the majority of published reports focus on YY1 levels, little has been reported on the expression and activity of YY1 family member Yin Yang 2 (YY2). YY1 and YY2 share more than 50% homologies in DNA and amino acid sequences and share the same C-terminal zinc finger domains involved in DNA binding. This survey of the reported literature revealed that the antibodies used in published immunohistochemistry analyses were not uniquely specific for YY1. Most were likely cross-reactive with YY2. Furthermore, data from the Human Protein Atlas regarding YY1 and YY2 expression in various cancers were generated using antibodies that did not discriminate between YY1 and YY2. This review analyzed the commercially available antibodies listed against YY1 and YY2 and determined their cross-reactivities. A summary is of the published studies on the expression levels of YY1 in human cancers and their potential cross-reactivities with YY2 is also provided. Well-documented monospecific antibodies to both YY1 and YY2 have to be developed and used when examining the expression levels of YY1 and YY2 in human cancers to elucidate the accurate relationship between them and clinical significance of each.