UHRF1 Expression Research Articles

YTHDF1 promotes gallbladder cancer progression via post-transcriptional regulation of the m6A/UHRF1 axis.

Gallbladder cancer is a rare but fatal malignancy. However, the mechanisms underlying gallbladder carcinogenesis and its progression are poorly understood. The function of m6A modification and its regulators was still unclear for gallbladder cancer. The current study seeks to investigate the function of YTH m6A RNA-binding protein 1 (YTHDF1) in gallbladder cancer. Transcriptomic analysis and immunochemical staining of YTHDF1 in gallbladder cancer tissues revealed its upregulation compared to paracancerous tissues. Moreover, YTHDF1 promotes the proliferation assays, Transwell migration assays, and Transwell invasion assays of gallbladder cancer cells invitro. And it also increased tumour growth in xenograft mouse model and metastases in tail vein injection model invivo. Invitro, UHRF1 knockdown partly reversed the effects of YTHDF1 overexpression. Mechanistically, dual-luciferase assays proved that YTHDF1 promotes UHRF1 expression via direct binding to the mRNA 3'-UTR in a m6A-dependent manner. Overexpression of YTHDF1 enhanced UHRF1 mRNA stability, as demonstrated by mRNA stability assays, and Co-IP studies confirmed a direct interaction between YTHDF1 and PABPC1. Collectively, these findings provide new insights into the progression of gallbladder cancer as well as a novel post-transcriptional mechanism of YTHDF1 via stabilizing target mRNA.

Clinicopathological Impact of CPA4, UHRF1, Glypican-1, and CD90 Expression in Lung Adenocarcinoma and Epithelioid Malignant Mesothelioma

Clinicopathological Impact of CPA4, UHRF1, Glypican-1, and CD90 Expression in Lung Adenocarcinoma and Epithelioid Malignant Mesothelioma

Upregulation of UHRF1 Promotes PINK1-mediated Mitophagy to Alleviates Ferroptosis in Diabetic Nephropathy.

Diabetic nephropathy (DN) is a common diabetic complication. Studies show that mitophagy inhibition induced-ferroptosis plays a crucial role in DN progression. UHRF1 is associated with mitophagy and is highly expression in DN patients, however, the effect of UHRF1 on DN is still unclear. Thus, in this study, we aimed to investigate whether UHRF1 involves DN development by the mitophagy/ferroptosis pathway. We overexpressed UHRF1 using an adeno-associated virus 9 (AAV9) system in high-fat diet/streptozotocin-induced diabetic mice. Renal function index, pathological changes, mitophagy factors, and ferroptosis factors were detected in vivo. High-glucose cultured human renal proximal tubular (HK-2) cells were used as in vitro models to investigate the mechanism of UHRF1 in DN. We found that diabetic mice exhibited kidney damage, which was alleviated by UHRF1 overexpression. UHRF1 overexpression promoted PINK1-mediated mitophagy and inhibited the expression of thioredoxin interacting protein (TXNIP), a factor associated with mitochondrial dysfunction. Additionally, UHRF1 overexpression alleviated lipid peroxidation and free iron accumulation, and upregulated the expression of GPX4 and Slc7a11, indicating the inhibition effect of UHRF1 overexpression on ferroptosis. We further investigated the mechanism of UHRF1 in the mitophagy/ferroptosis pathway in DN. We found that UHRF1 overexpression promoted PINK1-mediated mitophagy via inhibiting TXNIP expression, thus suppressing ferroptosis. These findings confirmed that upregulation of UHRF1 expression alleviates DN, indicating that UHRF1 has a reno-protective effect against DN.

UHRF1 is a mediator of KRAS driven oncogenesis in lung adenocarcinoma

KRAS is a frequent driver in lung cancer. To identify KRAS-specific vulnerabilities in lung cancer, we performed RNAi screens in primary spheroids derived from a Kras mutant mouse lung cancer model and discovered an epigenetic regulator Ubiquitin-like containing PHD and RING finger domains 1 (UHRF1). In human lung cancer models UHRF1 knock-out selectively impaired growth and induced apoptosis only in KRAS mutant cells. Genome-wide methylation and gene expression analysis of UHRF1-depleted KRAS mutant cells revealed global DNA hypomethylation leading to upregulation of tumor suppressor genes (TSGs). A focused CRISPR/Cas9 screen validated several of these TSGs as mediators of UHRF1-driven tumorigenesis. In vivo, UHRF1 knock-out inhibited tumor growth of KRAS-driven mouse lung cancer models. Finally, in lung cancer patients high UHRF1 expression is anti-correlated with TSG expression and predicts worse outcomes for patients with KRAS mutant tumors. These results nominate UHRF1 as a KRAS-specific vulnerability and potential target for therapeutic intervention.

Berberine stimulates lysosomal AMPK independent of PEN2 and maintains cellular AMPK activity through inhibiting the dephosphorylation regulator UHRF1.

Aim: AMPK is the key regulatory kinase mediating the effect of berberine (BBR) and metformin on metabolic improvement. The present study investigated the mechanism of BBR on AMPK activation at low doses, which was different from that of metformin. Methods: Lysosomes were isolated, and AMPK activity assay was performed. PEN2, AXIN1 and UHRF1 were investigated through gain/loss of function approaches, including overexpression, RNA interfering and CRISPR/Cas9-mediated gene knockout. Immunoprecipitation was utilized for detecting the interaction of UHRF1 and AMPKα1 after BBR treatment. Results: BBR activated lysosomal AMPK, but weaker than metformin. AXIN1 mediated BBR's effect on lysosomal AMPK activation, while PEN2 did not. BBR, but not metformin, decreased UHRF1 expression by promoting its degradation. BBR reduced the interaction between UHRF1 and AMPKα1. And overexpression of UHRF1 abolished the effect of BBR on AMPK activation. Conclusion: BBR activated lysosomal AMPK as dependent on AXIN1, but not PEN2. BBR maintained cellular AMPK activity by reducing UHRF1 expression and its interaction with AMPKα1. The mode of action of BBR was different from that of metformin on AMPK activation.

Lenvatinib inhibited HCC cell migration and invasion through regulating the transcription and ubiquitination of UHRF1 and DNMT1

Hepatocellular carcinoma (HCC) is one of the most common causes of malignancy-related deaths. Lenvatinib, as a multi-targeted tyrosine kinase inhibitor, has gained increasing attention for its antitumor activity. However, the effect and mechanisms of Lenvatinib on HCC metastasis are virtually unknown. In this study, we revealed that Lenvatinib inhibited HCC cell motility and epithelial mesenchymal transition (EMT), along with cell adhesion and extension. Concomitant high DNMT1 and UHRF1 mRNA levels were in HCC patients and indicated worse prognosis. On the one hand, Lenvatinib modulated the transcription of UHRF1 and DNMT1via negatively regulation of ERK/MAPK pathway. On the other hand, Lenvatinib downregulated DNMT1 and UHRF1 expression by promoting their protein degradation through ubiquitin–proteasome pathway, consequently, resulting in upregulation of E-Cadherin. Moreover, Lenvatinib attenuated Huh7 cell adhesion and metastasis in vivo. Our findings provided insight into the intriguing molecular mechanisms regarding the anti-metastasis effect of Lenvatinib in HCC.

WDR79 promotes aerobic glycolysis of pancreatic ductal adenocarcinoma (PDAC) by the suppression of SIRT4.

Pancreatic cancer (PC) is an aggressive malignant disease. Pancreatic ductal adenocarcinoma (PDAC) is a main type of PDAC. The inhibition of aerobic glycolysis in PC cells is one of the approaches to treat PDAC. WD repeat protein 79 (WDR79) acts as a scaffold protein and is involved in several physiological processes. Since WDR79 affects the progression of several types of cancers, whereas its role in PDAC remains unclear. This study was aimed to investigate the role of WDR79 in the progression of PDAC and clarify the mechanism. We found that WDR79 was highly expressed in PDAC cells. Knockdown of WDR79 inhibited the growth as well as the motility of PDAC cells, while overexpression of WDR79 contributed to the growth and motility. The ablation of WDR79 restrained aerobic glycolysis of PDAC cells. Mechanically, we found that WDR79 depletion increased SIRT4 expression by suppressing UHRF1 expression, which counteracted the function of WDR79 in PDAC. We thought that WDR79 could serve as a target for treating PDAC.

The vicious circle of UHRF1 down-regulation and KEAP1/NRF2/HO-1 pathway impairment promotes oxidative stress-induced endothelial cell apoptosis in diabetes.

Oxidative stress is recognized as a key factor in the induction of endothelial dysfunction in diabetes. However, the specific mechanisms have not been fully elucidated. We herein hypothesized that ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) might have a role in oxidative stress-induced endothelial cell (EC) apoptosis in diabetes. Western blot, qPCR, wound healing assay, apoptosis assay, reactive oxygen species (ROS) detection, dual-luciferase reporter assay, methylation-specific PCR, bisulfite sequencing PCR and chromatin immunoprecipitation assay were performed. UHRF1 expression levels were significantly decreased in endothelial colony-forming cells derived from peripheral blood of participants with type 2 diabetes compared with individuals without diabetes. ECs treated with high glucose, palmitate or hydrogen peroxide in vitro also exhibited decreased UHRF1 protein levels. Silencing of UHRF1 led to decreased migration ability and increased apoptosis and ROS production in ECs, which might be related to impaired Kelch-like ECH-associated protein 1 (KEAP1)/nuclear factor erythroid 2-related factor 2 (NRF2)/haeme oxygenase-1 pathway. Mechanistically, UHRF1 is closely implicated in epigenetic regulation of chromatin modification status at KEAP1 genomic locus via histone acetylation. NRF2 down-regulation in turn inhibits UHRF1 protein level, which might be due to increased ROS generation. Diabetes-induced oxidative stress can mediate down-regulation of UHRF1, which enhances ROS production by regulating KEAP1/p-NRF2 pathway through histone acetylation and might also form a self-perpetuating feedback loop with KEAP1/p-NRF2 to further promote oxidative stress-induced apoptosis of ECs in diabetes.

Plumbagin downregulates UHRF1, p-Akt, MMP-2 and suppresses survival, growth and migration of cervical cancer CaSki cells

Plumbagin is a natural compound known to impede growth of cancerous cells. However, anti-cervical cancer effects of plumbagin and its underlying molecular mechanism still remains elusive. In this study, plumbagin reduced the viability of CaSki cells in a concentration dependent manner and suppressed their colony formation potential. It led to G2/M phase arrest with downregulation of E2F1 and upregulation of p21. Plumbagin reduced mitochondrial membrane potential and concomitantly increased the percentage of apoptotic cells as revealed by annexin V-propidium iodide staining. Real Time PCR and western blotting confirmed that plumbagin induced apoptosis by reducing the expression of pAkt, procaspase 9 and full-length PARP. Furthermore, scratch assay showed that plumbagin suppressed migratory potential of CaSki cells which could be due to the reduced expression and activity of MMP-2 and upregulation of TIMP2. Interestingly, plumbagin also downregulated UHRF1 expression. Transient silencing of UHRF1 like plumbagin, induced G2/M phase arrest, enhanced apoptosis and suppressed metastasis of CaSki cells suggesting the role of UHRF1 in mediating anti-cancer activities of plumbagin. Plumbagin at IC20 (1 μM) interacted synergistically with cisplatin and reduced its IC50 value by 13.23 fold with improved effectivity as revealed by augmented apoptosis in CaSki cells.

UHRF1 overexpression promotes osteosarcoma metastasis through altered exosome production and AMPK/SEMA3E suppression

Loss-of-function mutations at the retinoblastoma (RB1) gene are associated with increased mortality, metastasis, and poor therapeutic outcome in several cancers, including osteosarcoma. However, the mechanism(s) through which RB1 loss worsens clinical outcome remains understudied. Ubiquitin-like with PHD and Ring Finger domains 1 (UHRF1) has been identified as a critical downstream effector of the RB/E2F signaling pathway that is overexpressed in various cancers. Here, we determined the role and regulatory mechanisms of UHRF1 in rendering osteosarcoma cells more aggressive. Higher UHRF1 expression correlated with malignancy in osteosarcoma cell lines, clinical samples, and genetically engineered mouse models. Gain- and loss-of-function assays revealed that UHRF1 has cell-intrinsic and extrinsic functions promoting cell proliferation, migration, invasion, angiogenesis, and metastasis. UHRF1 overexpression induced angiogenesis by suppressing AMPK activation and Semaphorin 3E (SEMA3E) expression. Further, UHRF1-mediated migration and metastasis resulted, at least in part, through altered expression of extracellular vesicles and their cargo, including urokinase-type plasminogen activator (uPA). Novel osteosarcoma genetically engineered mouse models confirmed that knocking out Uhrf1 considerably decreased metastasis and reversed the poorer survival associated with Rb1 loss. This presents a new mechanistic insight into RB1 loss-associated poor prognosis and novel oncogenic roles of UHRF1 in the regulation of angiogenesis and exosome secretion, both critical for osteosarcoma metastasis. This provides substantial support for targeting UHRF1 or its downstream effectors as novel therapeutic options to improve current treatment for osteosarcoma.

Epigenetic regulator UHRF1 orchestrates proinflammatory gene expression in rheumatoid arthritis in a suppressive manner.

Rheumatoid arthritis (RA) is characterized by chronic synovial inflammation with aberrant epigenetic alterations, eventually leading to joint destruction. However, the epigenetic regulatory mechanisms underlying RA pathogenesis remain largely unknown. Here, we showed that ubiquitin-like containing PHD and RING finger domains 1 (UHRF1) is a central epigenetic regulator that orchestrates multiple pathogeneses in RA in a suppressive manner. UHRF1 expression was remarkably upregulated in synovial fibroblasts (SFs) from arthritis model mice and patients with RA. Mice with SF-specific Uhrf1 conditional knockout showed more severe arthritic phenotypes than littermate controls. Uhrf1-deficient SFs also exhibited enhanced apoptosis resistance and upregulated expression of several cytokines, including Ccl20. In patients with RA, DAS28, CRP, and Th17 accumulation and apoptosis resistance were negatively correlated with UHRF1 expression in synovium. Finally, Ryuvidine administration stabilized UHRF1 ameliorated arthritis pathogeneses in a mouse model of RA. This study demonstrated that UHRF1 expressed in RA SFs can contribute to negative feedback mechanisms that suppress multiple pathogenic events in arthritis, suggesting that targeting UHRF1 could be one of the therapeutic strategies for RA.

Comprehensive Pan-Cancer Analysis Reveals the Role of UHRF1-Mediated DNA Methylation and Immune Infiltration in Renal Cell Carcinoma.

Ubiquitin-like PHD and ring finger domain protein 1 (UHRF1) are members of the multifunctional UHRF family, which can participate in DNA methylation change and histone posttranslational change through particular domains and participate in the event and development of tumors. The purpose of this study was to decide the molecular traits and potential medicine-based importance of UHRF1 that helped settle methylated immune infiltration in generalized cancer by carefully studying the relationship between UHRF1 expression and a variety of tumors and to further check for truth the functional role of UHRF1 in kidney-related cancer. A comprehensive analysis of UHRF1 in 33 cancers was performed based on TCGA database. This research involves analysis of mRNA expression profiles, prognostic value, immune infiltration, immune neoantigens, TMB, microsatellite instability, DNA methylation, and gene set enrichment analysis (GSEA). Both immune infiltration and DNA methylation were used to evaluate the importance and method of UHRF1 in renal cancer. The results showed that tumor tissue had higher expression level of UHRF1 than usual tissue. The high expression level of UHRF1 is related to the survival rate of renal cancer. UHRF1 expression was associated with tumor mutation load and microsatellite instability in different cancer types, and enrichment analysis identified terminology and pathways associated with UHRF1. This study showed that UHRF1 plays an important role in the group of objects and development of 33 tumors. UHRF1 may serve as a biomarker of immune infiltration and poor outlook of cancer.

Yaobishu Regulates Inflammatory, Metabolic, Autophagic, and Apoptosis Pathways to Attenuate Lumbar Disc Herniation.

Objective Here, we aimed to explore the main mechanism of Yaobishu (YBS) in lumbar disc herniation (LDH). Methods and Results Eighteen compounds that might act on LDH were obtained through a combination of network pharmacology prediction and identification by high-performance liquid chromatography-mass spectrometry. The key compounds were palmitic acid and trans-4-hydroxy-3-methoxycinnamate (cinnamate). KEGG analysis demonstrated that palmitic acid target genes mainly regulate the PPAR signaling pathway, Ras signaling pathway, and fatty acid metabolism. Cinnamate target genes were primarily involved in chemical carcinogenesis-receptor activation, lipid and atherosclerosis, the HIF-1 signaling pathway, and nitrogen metabolism. The rat LDH model was constructed using autologous nucleus pulposus tissue implantation. Differential expression gene (DEGs) related to metabolism (CDKN1A and UHRF1), inflammation (S100A9 and SOCS3), autophagy (DCN and LEPR), and apoptosis (CTSW and BCL2A1) in dorsal root ganglion (DRG) tissues of the control and LDH groups was evaluated by RNA-Seq. TNF-α stimulated DRG neuronal cells were used to establish an in vitro LDH model. YBS, palmitic acid, and cinnamate reduced the expression of substance P, CGRP, S100A9, CTSW, and cleaved caspase-3, while enhancing the expression of CDKN1A, UHRF1, PCNA, Ki67, SOCS3, DCN, LEPR, and BCL2A1, as well as telomerase activity. Pearson's correlation analysis confirmed that DCN was positively correlated with BCL2A1, indicating that autophagy might be negatively correlated with apoptosis in LDH. YBS, palmitic acid, and cinnamate reduced the Siegal neurological score and serum IL-1β and IL-18 levels, while increasing changes in the hind paw mechanical withdrawal threshold. The RNA-Seq results further showed that YBS downregulated S100A9 and CTSW expression, while upregulating SOCS3, CDKN1A, UHRF1, DCN, LEPR, and BCL2A1 expression. Conclusion YBS and its compounds, palmitic acid, and cinnamate, attenuated LDH by regulating the inflammatory, metabolic, autophagic, and apoptotic pathways. Our results might improve the theoretical and experimental basis for clinical applications of LDH disease treatment.

The long non-coding RNA UPAT promotes gastric cancer cell progression via UHRF1.

LncRNA ubiquitin-like with PHD and RING finger domains 1 (UHRF1) protein associated transcript (UPAT) regulates the progression of many cancers. However, its role in gastric cancer (GC) is less frequently reported. In the context of the promoting effect of lncRNA on modulating GC progression, detailed insights into the role and underlying mechanism of UPAT in GC are the foothold in this study. Overall survival was calculated. The mRNA expressions of UPAT and UHRF1 were measured by qRT-PCR, and the protein expressions of UHRF1, Cyclin D1 and cleaved caspase-3 were determined by western blot. Cell viability, growth, migration and invasion were assessed by CCK-8, colony formation, wound healing and Transwell assays, respectively. Apoptosis rate and cell cycle were assayed by flow cytometry. UPAT was overexpressed in GC tissue and cell lines. Decreased UPAT level was associated with higher overall survival. Down-regulation of UPAT diminished cell proliferation, Cyclin D1 expression, and migration and invasion rates, increased apoptosis rate and cleaved caspase-3 expression, and blocked cell cycle in AGS and NCI-N87 cells. UPAT expression in GC was positively correlated with UHRF1 expression. UHRF1 overexpression offset the inhibitory effects of UPAT down-regulation on cell proliferation, migration, invasion and cell cycle, and partially reversed the positive effect of UPAT down-regulation on apoptosis. UPAT might positively regulate the progression of GC via interacting with UHRF1. The UHRF1/UPAT axis revealed in the present study may provide a promising approach to intervene in the progression of GC.

UHRF1 shapes both the trophoblast invasion and decidual macrophage differentiation in early pregnancy.

Trophoblasts play critical roles in establishment and maintenance of a normal pregnancy. Their dysfunction in early pregnancy is closely related to pregnancy-related diseases, including recurrent pregnancy loss (RPL). Epigenetic modifications dynamically change during pregnancy; however, the role of the epigenetic modifier UHRF1 in trophoblast regulation remains unknown. This is the first study to show that UHRF1 expression was localized in the cytoplasm of cytotrophoblasts, syncytiotrophoblasts, and villi columns, and decreased in the villi of patients with RPL. The invasion and cell viability in a UHRF1knockdown trophoblast cell line were significantly decreased. In addition, the mRNA expression profiles of Swan71 cells were partially altered by UHRF1knockdown. The altered immune-related genes were screened out and the pro-inflammatory TH1-type chemokine/cytokines CXCL2 and IL-1β were identified as the most promising targets of UHRF1 in the trophoblasts, which were significantly increased in the UHRF1knockdown Swan71 cells, villi, and serum from patients with RPL. The macrophages treated with the supernatants of UHRF1knockdown Swan71 cells were polarized to the M1 phenotype and secreted high levels of pro-inflammatory cytokines, which might be driven by the activated MyD88/NF-κB signaling pathway and mediated by the increased expression of CXCR2 and IL-1R1 (CXCL2 and IL-1β receptors, respectively). In addition, the supernatants of UHRF1knockdown Swan71 cells showed stronger chemotaxis to macrophages than those from the controls. Our findings highlight the previously unknown roles of UHRF1 as one of the key regulators on the trophoblasts and their cross-talk with local immune cells, and demonstrate a potential approach for RPL intervention.

SHMT2 Drives the Progression of Colorectal Cancer by Regulating UHRF1 Expression.

Introduction Serine hydroxymethyltransferase 2 (SHMT2) has a critical role in serine-glycine metabolism to drive cancer cell proliferation. Yet, the function of SHMT2 in tumorigenesis, especially in human colorectal cancer (CRC) progression, remains largely unclear. Materials and Methods CRC and paired normal samples were collected in the Department of Colorectal Surgery, Xinhua Hospital, Shanghai Jiao Tong University School of Medicine, and assessed by real-time polymerase chain reaction (qPCR) analysis, western blot (WB), and immunohistochemistry (IHC). Moreover, SHMT2 expression in human CRC cells was identified by qPCR and WB. The CRC cell proliferation, migration, and invasion after SHMT2 knockdown were explored through in vitro and in vivo assays. mRNA-seq assays were used to investigate the underlying mechanisms behind the SHMT2 function. Results It was found that SHMT2 mRNA and protein were overexpressed in CRC tissue compared to the levels in normal mucosa. Positive expression of SHMT2 was significantly correlated with TNM stage and lymph node metastasis, and elevated expression of SHMT2 resulted as an independent prognostic factor in patients with CRC. SHMT2 knockdown impaired the proliferation of CRC in vitro and in vivo and induced cell cycle arrest by regulating UHRF1 expression. Conclusion Taken together, our findings reveal that UHRF1 is a novel target gene of SHMT2, which can be used as a potential therapeutic strategy for CRC therapy.

Crosstalk between macrophage-derived PGE2 and tumor UHRF1 drives hepatocellular carcinoma progression.

Background: Tumor-associated macrophages (TAMs) and dysregulated tumor epigenetics contribute to hepatocellular carcinoma (HCC) progression. However, the mechanistic interactions between TAMs and tumor epigenetics remain poorly understood.Methods: Immunohistochemistry and multiplexed fluorescence staining were performed to evaluate the correlation between TAMs numbers and UHRF1 expression in human HCC tissues. PGE2 neutralizing antibody and COX-2 inhibitor were used to analyze the regulation of TAMs isolated from HCC tissues on UHRF1 expression. Multiple microRNA prediction programs were employed to identify microRNAs that target UHRF1 3'UTR. Luciferase reporter assay was applied to evaluate the regulation of miR-520d on UHRF1 expression. Chromatin immunoprecipitation (ChIP) assays were performed to assess the abundance of H3K9me2 in the KLF6 promoter and DNMT1 in the CSF1 promoter regulated by UHRF1. The functional roles of TAM-mediated oncogenic network in HCC progression were verified by in vitro colony formation assays, in vivo xenograft experiments and analysis of clinical samples.Results: Here, we find that TAMs induce and maintain high levels of HCC UHRF1, an oncogenic epigenetic regulator. Mechanistically, TAM-derived PGE2 stimulates UHRF1 expression by repressing miR-520d that targets the 3'-UTR of UHRF1 mRNA. In consequence, upregulated UHRF1 methylates H3K9 to diminish tumor KLF6 expression, a tumor inhibitory transcriptional factor that directly transcribes miR-520d. PGE2 reduces KLF6 occupancy in the promoter of miR-520d, dampens miR-520d expression, and sustains robust UHRF1 expression. Moreover, UHRF1 promotes CSF1 expression by inducing DNA hypomethylation of the CSF1 promoter and supports TAM accumulation.Conclusions: Capitalizing on studies on HCC cells and tissues, animal models, and clinical information, we reveal a previously unappreciated TAM-mediated oncogenic network via multiple reciprocal enforcing molecular nodes. Targeting this network may be an approach to treat HCC patients.

Nfe2l2 Regulates Metabolic Rewiring and Epigenetic Reprogramming in Mediating Cancer Protective Effect by Fucoxanthin.

Fucoxanthin (FX) is a carotenoid with many pharmaceutical properties due to its antioxidant/anti-inflammatory and epigenetic effects. NFE2L2 is involved in the defense against oxidative stress/inflammation-mediated diseases, like anticancer effects elicited by phytochemicals including FX. However, the role of FX and NFE2L2 in metabolic rewiring, epigenomic reprogramming, and transcriptomic network in blocking pro-tumorigenic signaling and eliciting cancer-protective effects remains unknown. Herein, we utilized multi-omics approaches to evaluate the role of NFE2L2 and the impact of FX on tumor promoter TPA-induced skin cell transformation. FX blocked TPA-induced ROS and oxidized GSSG/reduced GSH in Nfe2l2wild-type(WT) but not Nfe2l2-knockdown (KD) cells. Both Nfe2l2 KD and TPA altered cellular metabolisms and metabolites which are tightly coupled to epigenetic machinery. The suppressive effects of FX on TPA-enhancedSAM/SAH was abrogated by Nfe2l2 KD indicating Nfe2l2 plays a critical role in FX-mediated metabolic rewiring and its potential consequences on epigenetic reprogramming. Epigenomic CpG methyl-seq revealed that FX attenuated TPA-induced differentially methylated regions (DMRs) of Uhrf1 and Dnmt1 genes. Transcriptomic RNA-seq showed that FX abrogated TPA-induced differentially expressed genes (DEGs) of Nfe2l2-related genes Nqo1, Ho1, and Keap1. Associative analysis of DEGs and DMRs identified that the mRNA expressions of Uhrf1 and Dnmt1 were correlated with the promoter CpG methylation status. Chromatin immunoprecipitation assay showed that FX restored Uhrf1 expression by regulating H3K27Me3 enrichment in the promoter region. In this context, FX/Nfe2l2's redox signaling drives metabolic rewiring causing epigenetic and transcriptomic reprogramming potentially contributing to the protection of TPA-induced JB6 cellular transformation skin cancer model. Graphical abstract.

UHRF1 Could Be a Prognostic Biomarker and Correlated with Immune Cell Infiltration in Hepatocellular Carcinoma.

ObjectiveThis study was performed to investigate the relationship among UHRF1 expression, its biological function and immune infiltration in human hepatocellular carcinoma (HCC).MethodsGene Expression Profiling Interactive Analysis (GEPIA), Oncomine, and The Cancer Genome Atlas (TCGA) databases were used to analyze UHRF1 expression between HCC and normal tissues. Subsequently, GEPIA, TCGA-Portal, Kaplan–Meier Plotter, Protein Atlas and SurvExpress databases were utilized for survival analysis. UHRF1 co-expression genes were identified via the cBioPortal and LinkedOmics databases. Further, gene ontology (GO) analysis as well as Kyoto Encyclopedia of Genes and Genomes (KEGG) analysis were performed. Protein–protein interaction (PPI) networks was constructed by STRING database and Cytoscape 3.7.1. Single-sample gene set enrichment analysis (ssGSEA) and CIBERSORT algorithm were employed to assess the correlation between UHRF1 and tumor immune infiltrates on TCGA database. TIMER 2.0 database was used to explore the correlation of UHRF1 expression and immune infiltration level in HCC. Additionally, RT-qPCR was used to analyze the expression of UHRF1 and the relative genes in HCC cell lines.ResultsExpression level of UHRF1 was upregulated in HCC tissues compared with paired normal tissues (P < 0.05 in GEPIA; P = 1.78E−6 in Oncomine; and P < 0.0001 in TCGA). Its high expression was significantly related with a shorter overall survival in five databases (P < 0.05). Function enrichment analysis demonstrated that functions of UHRF1 concentrated in cell division process and cell cycle (P < 0.05). High UHRF1 expression exhibited dysregulated immune infiltration (ie, neutrophils, eosinophils, dendritic cells resting, macrophages M2, macrophages M0) and poor survival of high UHRF1 expression was tight correlated with immune infiltration status. Moreover, TP53 mutation can lead to high expression of UHRF1 (P = 4.2E−10).ConclusionUHRF1 might function as an oncogene via inducing dysregulated immune infiltration in HCC and was identified as a novel prognostic biomarker and potential therapeutic target for HCC.

TIP60 governs the auto‑ubiquitination of UHRF1 through USP7 dissociation from the UHRF1/USP7 complex.

Tat interactive protein, 60 kDa (TIP60) is an important partner of ubiquitin-like, containing PHD and RING finger domains 1 (UHRF1), ensuring various cellular processes through its acetyltransferase activity. TIP60 is believed to play a tumor suppressive role, partly explained by its downregulated expression in a number of cancers. The aim of the present study was to investigate the role and mechanisms of action of TIP60 in the regulation of UHRF1 expression. The results revealed that TIP60 overexpression downregulated the UHRF1 and DNA methyltransferase 1 (DNMT1) expression levels. TIP60 interfered with USP7-UHRF1 association and induced the degradation of UHRF1 in an auto-ubiquitination-dependent manner. Moreover, TIP60 activated the p73-mediated apoptotic pathway. Taken together, the data of the present study suggest that the tumor suppressor role of TIP60 is mediated by its regulation to UHRF1.