Search Results (37)

Lupus nephritis (LN) is a severe form of systemic lupus erythematosus (SLE), characterized by inflammation in the renal glomeruli and tubules. Previous research has demonstrated that dihydroartemisinin (DHA) can reduce inflammatory damage in LN mouse models. Oxymatrine, which has similar biological properties to DHA, may also provide therapeutic benefits. This study aims to investigate the effects of oxymatrine on LN using a murine model and examines its molecular mechanisms through an analysis of microarray datasets from LN patients. The analysis identified differentially expressed genes (DEGs) in renal tissues, regulated by the transcription factor Yin Yang 1 (YY1), which was found to be significantly upregulated in LN patient kidneys. The results indicate that oxymatrine targets the YY1/IL-6/STAT3 signaling pathway. In cell models simulating renal inflammation, oxymatrine reduced YY1 expression and inhibited the secretion of inflammatory factors (IFs), thereby diminishing inflammation. YY1 is crucial in modulating IFs’ secretion and contributing to LN pathogenesis. Additionally, oxymatrine’s interaction with YY1, leading to its downregulation, appears to be a key mechanism in alleviating LN symptoms. These findings support oxymatrine as a promising therapeutic agent for LN, offering new avenues for treating this autoimmune kidney disorder. Full article

Acute lymphoblastic leukemia (ALL) is the most common childhood cancer. Current chemotherapy treatment regimens have improved survival rates to approximately 80%; however, resistance development remains the primary cause of treatment failure, affecting around 20% of cases. Some studies indicate that loss of the phosphatase and tensin homolog (PTEN) leads to deregulation of the phosphoinositide 3-kinase (PI3K)/protein kinase B (Akt) signaling pathway, increasing the expression of proteins involved in chemoresistance. PTEN loss results in deregulation of the nuclear factor kappa-light-chain-enhancer of activated B cells (NF-κB) and induces hypoxia-inducible factor 1-alpha (HIF-1α) expression in various cancers. Additionally, it triggers upregulation of the Yin Yang 1 (YY1) transcription factor, leading to chemoresistance mediated by glycoprotein p-170 (Gp-170). The aim of this study was to investigate the role of the PTEN/NF-κB axis in YY1 regulation via HIF-1α and its involvement in ALL. A PTEN inhibitor was administered in RS4;11 cells, followed by the evaluation of PTEN, NF-κB, HIF-1α, YY1, and Gp-170 expression, along with chemoresistance assessment. PTEN, HIF-1α, and YY1 expression levels were assessed in the peripheral blood mononuclear cells (PBMC) from pediatric ALL patients. The results reveal that the inhibition of PTEN activity significantly increases the expression of pAkt and NF-κB, which is consistent with the increase in the expression of HIF-1α and YY1 in RS4;11 cells. In turn, this inhibition increases the expression of the glycoprotein Gp-170, affecting doxorubicin accumulation in the cells treated with the inhibitor. Samples from pediatric ALL patients exhibit PTEN expression and higher HIF-1α and YY1 expression compared to controls. PTEN/Akt/NF-κB axis plays a critical role in the regulation of YY1 through HIF-1α, and this mechanism contributes to Gp-170-mediated chemoresistance in pediatric ALL. Full article

The transcription factor Yin Yang 1 (YY1) plays a pivotal role in the pathogenesis of glioblastoma multiforme (GBM), an aggressive form of brain tumor. This review systematically explores the diverse roles of YY1 overexpression and activities in GBM, including its impact on the tumor microenvironment (TME) and immune evasion mechanisms. Due to the poor response of GBM to current therapies, various findings of YY1-associated pathways in the literature provide valuable insights into novel potential targeted therapeutic strategies. Moreover, YY1 acts as a significant regulator of immune checkpoint molecules and, thus, is a candidate therapeutic target in combination with immune checkpoint inhibitors. Different therapeutic implications targeting YY1 in GBM and its inherent associated challenges encompass the use of nanoparticles, YY1 inhibitors, targeted gene therapy, and exosome-based delivery systems. Despite the inherent complexities of such methods, the successful targeting of YY1 emerges as a promising avenue for reshaping GBM treatment strategies, presenting opportunities for innovative therapeutic approaches and enhanced patient outcomes. Full article

Small-molecule positive allosteric modulator 1 (SPAM1), which targets pituitary adenylate cyclase-activating polypeptide receptor 1 (PAC1-R), has been found to have a neuroprotective effect, and the underlying mechanism was explored in this study. First, using a D-galactose (D-gal)-induced aging mouse model, we confirmed that SPAM1 improves the structure of the hippocampal dentate gyrus and restores the number of neurons. Compared with D-gal model mice, SPAM1-treated mice showed up-regulated expression of Sirtuin 6 (SIRT6) and Lamin B1 and down-regulated expression of YinYang 1 (YY1) and p16. A similar tendency was observed in senescent RGC-5 cells induced by long-term culture, indicating that SPAM1 exhibits significant in vitro and in vivo anti-senescence activity in neurons. Then, using whole-transcriptome sequencing and proteomic analysis, we further explored the mechanism behind SPAM1’s neuroprotective effects and found that SPAM is involved in the longevity-regulating pathway. Finally, the up-regulation of neurofilament light and medium polypeptides indicated by the proteomics results was further confirmed by Western blotting. These results help to lay a pharmacological network foundation for the use of SPAM1 as a potent anti-aging therapeutic drug to combat neurodegeneration with anti-senescence, neuroprotective, and nerve regeneration activity. Full article

During the last decade, we have witnessed several milestones in the treatment of various resistant cancers including immunotherapeutic strategies that have proven to be superior to conventional treatment options, such as chemotherapy and radiation. This approach utilizes the host’s immune response, which is triggered by cancer cells expressing tumor-associated antigens or neoantigens. The responsive immune cytotoxic CD8⁺ T cells specifically target and kill tumor cells, leading to tumor regression and prolongation of survival in some cancers; however, some cancers may exhibit resistance due to the inactivation of anti-tumor CD8⁺ T cells. One mechanism by which the anti-tumor CD8⁺ T cells become dysfunctional is through the activation of the inhibitory receptor programmed death-1 (PD-1) by the corresponding tumor cells (or other cells in the tumor microenvironment (TME)) that express the programmed death ligand-1 (PD-L1). Hence, blocking the PD-1/PD-L1 interaction via specific monoclonal antibodies (mAbs) restores the CD8⁺ T cells’ functions, leading to tumor regression. Accordingly, the Food and Drug Administration (FDA) has approved several checkpoint antibodies which act as immune checkpoint inhibitors. Their clinical use in various resistant cancers, such as metastatic melanoma and non-small-cell lung cancer (NSCLC), has shown significant clinical responses. We have investigated an alternative approach to prevent the expression of PD-L1 on tumor cells, through targeting the oncogenic transcription factor Yin Yang 1 (YY1), a known factor overexpressed in many cancers. We report the regulation of PD-L1 by YY1 at the transcriptional, post-transcriptional, and post-translational levels, resulting in the restoration of CD8⁺ T cells’ anti-tumor functions. We have performed bioinformatic analyses to further explore the relationship between both YY1 and PD-L1 in cancer and to corroborate these findings. In addition to its regulation of PD-L1, YY1 has several other anti-cancer activities, such as the regulation of proliferation and cell viability, invasion, epithelial–mesenchymal transition (EMT), metastasis, and chemo-immuno-resistance. Thus, targeting YY1 will have a multitude of anti-tumor activities resulting in a significant obliteration of cancer oncogenic activities. Various strategies are proposed to selectively target YY1 in human cancers and present a promising novel therapeutic approach for treating unresponsive cancer phenotypes. These findings underscore the distinct regulatory roles of YY1 and PD-L1 (CD274) in cancer progression and therapeutic response. Full article

Non-alcoholic fatty liver disease (NAFLD) is characterized by excessive lipid accumulation in the liver. Clarifying the molecular mechanism of lipid metabolism is crucial for the treatment of NAFLD. We examined miR-192-5p levels in the livers of mice in which NAFLD was induced via a high-fat diet (HFD), as well as in mouse primary hepatocytes and human HepG2 cells treated with free fatty acids (FFAs). MiR-192-5p inhibitor was administered to NAFLD mice and hepatocytes to verify the specific function of miR-192-5p in NAFLD. We validated the target gene of miR-192-5p and further illustrated the effects of this miRNA on the regulation of triglyceride (TG) metabolism. We found that miR-192-5p was significantly increased in the livers of NAFLD mice and FFA-treated hepatocytes. Inhibition of miR-192-5p increased the accumulation of hepatic TGs and aggravated hepatic steatosis in NAFLD mice. In FFA-treated hepatocytes, miR-192-5p inhibitors markedly increased TG content, whereas overexpression of miR-192-5p reduced TG levels. Yin Yang 1 (Yy1) was identified as the target gene of miR-192-5p, which regulates TG synthesis via the YY1/fatty-acid synthase (FASN) pathway. Our results demonstrated that miR-192-5p should be considered a protective regulator in NAFLD that can inhibit hepatic TG synthesis by targeting Yy1. Full article

YY1 is widely recognized as an intrinsically disordered transcription factor that plays a role in development of many cancers. In most cases, its overexpression is correlated with tumor progression and unfavorable patient outcomes. Our latest research focusing on the role of zinc ions in modulating YY1’s interaction with DNA demonstrated that zinc enhances the protein’s multimeric state and affinity to its operator. In light of these findings, changes in protein concentration appear to be just one element relevant to modulating YY1-dependent processes. Thus, alterations in zinc ion concentration can directly and specifically impact the regulation of gene expression by YY1, in line with reports indicating a correlation between zinc ion levels and advancement of certain tumors. This review concentrates on other potential consequences of YY1 interaction with zinc ions that may act by altering charge distribution, conformational state distribution, or oligomerization to influence its interactions with molecular partners that can disrupt gene expression patterns. Full article

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. Full article

In this study we analyzed the expression of Yin and Yang 1 protein (YY1), a member of the noncanonical PcG complexes, in AML patient samples and AML cell lines and the effect of YY1 downregulation on the AML differentiation block. Our results show that YY1 is significantly overexpressed in AML patient samples and AML cell lines and that YY1 knockdown relieves the differentiation block. YY1 downregulation in two AML cell lines (HL-60 and OCI-AML3) and one AML patient sample restored the expression of members of the CEBP protein family, increased the expression of extrinsic growth factors/receptors and surface antigenic markers, induced morphological cell characteristics typical of myeloid differentiation, and sensitized cells to retinoic acid treatment and to apoptosis. Overall, our data show that YY1 is not a secondary regulator of myeloid differentiation but that, if overexpressed, it can play a predominant role in myeloid differentiation block. Full article

Cancer represents a significant and persistent global health burden, with its impact underscored by its prevalence and devastating consequences. Whereas numerous oncogenes could contribute to cancer development, a group of transcription factors (TFs) are overactive in the majority of tumors. Targeting these TFs may also combat the downstream oncogenes activated by the TFs, making them attractive potential targets for effective antitumor therapeutic strategy. One such TF is yin yang 1 (YY1), which plays crucial roles in the development and progression of various tumors. In preclinical studies, YY1 inhibition has shown efficacy in inhibiting tumor growth, promoting apoptosis, and sensitizing tumor cells to chemotherapy. Recent studies have also revealed the potential of combining YY1 inhibition with immunotherapy for enhanced antitumor effects. However, clinical translation of YY1-targeted therapy still faces challenges in drug specificity and delivery. This review provides an overview of YY1 biology, its role in tumor development and progression, as well as the strategies explored for YY1-targeted therapy, with a focus on their clinical implications, including those using small molecule inhibitors, RNA interference, and gene editing techniques. Finally, we discuss the challenges and current limitations of targeting YY1 and the need for further research in this area. Full article

Yin Yang 1 (YY1) is a transcription factor that regulates epigenetic pathways and protein modifications. CP2c is a transcription factor that functions as an oncogene to regulate cell proliferation. YY1 is known to interact with CP2c to suppress CP2c’s transcriptional activity. This study aimed to investigate YY1 and CP2c expression in breast cancer and prognostic implications. In this study, YY1 and CP2c expression was evaluated using immunohistochemical staining, Western blot and RT-PCR assays. Of 491 patients with primary breast cancer, 138 patients showed YY1 overexpression. Luminal subtype and early stage were associated with overexpression (p < 0.001). After a median follow-up of 68 months, YY1 overexpression was found to be associated with a better prognosis (disease-free survival rates of 92.0% vs. 79.2%, p = 0.014). In Cox proportional hazards model, YY1 overexpression functioned as an independent prognostic factor after adjustment of hormone receptor/HER2 status and tumor size (hazard ratio of 0.50, 95% CI 0.26–0.98, p = 0.042). Quantitative analysis of YY1 and CP2c protein expression in tumors revealed a negative correlation between them. In conclusion, YY1 overexpression is a favorable prognostic biomarker in patients with breast cancer, and it has a negative correlation with CP2c at the protein level. Full article

Yin Yang 1 (YY1) is a well-known transcription factor that controls the expression of many genes and plays an important role in the occurrence and development of various cancers. We previously found that the human males absent on the first (MOF)-containing histone acetyltransferase (HAT) complex may be involved in regulating YY1 transcriptional activity; however, the precise interaction between MOF-HAT and YY1, as well as whether the acetylation activity of MOF impacts the function of YY1, has not been reported. Here, we present evidence that the MOF-containing male-specific lethal (MSL) HAT complex regulates YY1 stability and transcriptional activity in an acetylation-dependent manner. First, the MOF/MSL HAT complex was bound to and acetylated YY1, and this acetylation further promoted the ubiquitin–proteasome degradation pathway of YY1. The MOF-mediated degradation of YY1 was mainly related to the 146–270 amino acid residues of YY1. Further research clarified that acetylation-mediated ubiquitin degradation of YY1 mainly occurred through lysine 183. A mutation at the YY1K183 site was sufficient to alter the expression level of p53-mediated downstream target genes, such as CDKN1A (encoding p21), and it also suppressed the transactivation of YY1 on CDC6. Furthermore, a YY1K183R mutant and MOF remarkably antagonized the clone-forming ability of HCT116 and SW480 cells facilitated by YY1, suggesting that the acetylation–ubiquitin mode of YY1 plays an important role in tumor cell proliferation. These data may provide new strategies for the development of therapeutic drugs for tumors with high expression of YY1. Full article

YIN YANG 1 (YY1) encodes a dual-function transcription factor, evolutionary conserved between the animal and plant kingdom. In Arabidopsis thaliana, AtYY1 is a negative regulator of ABA responses and floral transition. Here, we report the cloning and functional characterization of the two AtYY1 paralogs, YIN and YANG (also named PtYY1a and PtYY1b) from Populus (Populus trichocarpa). Although the duplication of YY1 occurred early during the evolution of the Salicaceae, YIN and YANG are highly conserved in the willow tree family. In the majority of Populus tissues, YIN was more strongly expressed than YANG. Subcellular analysis showed that YIN-GFP and YANG-GFP are mainly localized in the nuclei of Arabidopsis. Stable and constitutive expression of YIN and YANG resulted in curled leaves and accelerated floral transition of Arabidopsis plants, which was accompanied by high expression of the floral identity genes AGAMOUS (AG) and SEPELLATA3 (SEP3) known to promote leaf curling and early flowering. Furthermore, the expression of YIN and YANG had similar effects as AtYY1 overexpression to seed germination and root growth in Arabidopsis. Our results suggest that YIN and YANG are functional orthologues of the dual-function transcription factor AtYY1 with similar roles in plant development conserved between Arabidopsis and Populus. Full article

Gabriele-de Vries syndrome is a rare autosomal dominant genetic disease caused by de novo pathogenic variants in the Yin Yang 1 (YY1) gene. Individuals with this syndrome present with multiple congenital anomalies, as well as a delay in development and intellectual disability. Herein, we report the case of a newborn male patient with a novel de novo pathogenic variant in the Guanine Nucleotide-Binding Protein, Alpha Stimulating (GNAS) gene, which was identified by whole-exome sequencing. Our patient suffered from a large open spinal dysraphism which was treated surgically immediately after birth. During the follow-up, facial dysmorphism, bladder and bowel incontinence, and mildly delayed motor and speech development were observed. Congenital central nervous system disorders were also confirmed radiologically. In this case report, we present our diagnostic and treatment approaches to this patient. To our knowledge, this is the first reported case of Gabriele-de Vries syndrome presenting with spinal dysraphism. Extensive genetic evaluation is the cornerstone in treatment of patients with suspected Gabriele-de Vries syndrome. However, in cases with potentially life-threatening conditions, surgery should be strongly considered. Full article

Human endogenous retroviruses (HERVs) are remnants of ancestral germline infections by exogenous retroviruses. Human endogenous retroviruses W family envelope gene (HERV-W env, also called ERVWE1), located on chromosome 7q21-22, encodes an envelope glycoprotein from the HERV-W family. Mounting evidence suggests that aberrant expression of ERVWE1 involves the etiology of schizophrenia. Moreover, the genetic and morphological studies indicate that dendritic spine deficits may contribute to the onset of schizophrenia. Here, we reported that ERVWE1 changed the density and morphology of the dendritic spine through inhibiting Wingless-type (Wnt)/c-Jun N-terminal kinases (JNK) non-canonical pathway via miR-141-3p in schizophrenia. In this paper, we found elevated levels of miR-141-3p and a significant positive correlation with ERVWE1 in schizophrenia. Moreover, serum Wnt5a and actin-related protein 2 (Arp2) levels decreased and demonstrated a significant negative correlation with ERVWE1 in schizophrenia. In vitro experiments disclosed that ERVWE1 up-regulated miR-141-3p expression by interacting with transcription factor (TF) Yin Yang 1 (YY1). YY1 modulated miR-141-3p expression by binding to its promoter. The luciferase assay revealed that YY1 enhanced the promoter activity of miR-141-3p. Using the miRNA target prediction databases and luciferase reporter assays, we demonstrated that miR-141-3p targeted Wnt5a at its 3’ untranslated region (3′ UTR). Furthermore, ERVWE1 suppressed the expression of Arp2 through non-canonical pathway, Wnt5a/JNK signaling pathway. In addition, ERVWE1 inhibited Wnt5a/JNK/Arp2 signal pathway through miR-141-3p. Finally, functional assays showed that ERVWE1 induced the abnormalities in hippocampal neuron morphology and spine density through inhibiting Wnt/JNK non-canonical pathway via miR-141-3p in schizophrenia. Our findings indicated that miR-141-3p, Wnt5a, and Arp2 might be potential clinical blood-based biomarkers or therapeutic targets for schizophrenia. Our work also provided new insight into the role of ERVWE1 in schizophrenia pathogenesis. Full article