A positive feedback loop of CENPU/E2F6/E2F1 facilitates proliferation and metastasis via ubiquitination of E2F6 in hepatocellular carcinoma
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ABSTRACT:
SUBMITTER: Liu Y
PROVIDER: S-EPMC9274498 | biostudies-literature |
REPOSITORIES: biostudies-literature
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Project description:Hepatocellular carcinoma (HCC) accounts for one of the leading causes of cancer-related death, and is attributed to the dysregulation of genes involved in genome stability. DDX11, a DNA helicase, has been implicated in rare genetic disease and human cancers. Yet, its clinical value, biological function, and the underlying mechanism in HCC progression are not fully understood. Here, we show that DDX11 is upregulated in HCC and exhibits oncogenic activity via EZH2/p21 signaling. High expression of DDX11 is significantly correlated with poor outcomes of HCC patients in two independent cohorts. DDX11 overexpression increases HCC cell viabilities and colony formation, whereas DDX11 knockdown arrests cells at G1 phase without alteration of p53 expression. Ectopic expression of DDX11 reduces, while depletion of DDX11 induces the expression of p21. Treatment of p21 siRNA markedly attenuates the cell growth suppression caused by DDX11 silence. Further studies reveal that DDX11 interacts with EZH2 in HCC cells to protect it from ubiquitination-mediated protein degradation, consequently resulting in the downregulation of p21. In addition, E2F1 is identified as one of the upstream regulators of DDX11, and forms a positive feedback loop with EZH2 to upregulate DDX11 and facilitate cell proliferation. Collectively, our data suggest DDX11 as a promising prognostic factor and an oncogene in HCC via a E2F1/DDX11/EZH2 positive feedback loop.
| S-EPMC7892623 | biostudies-literature
Project description:Rapid tumor progression, metastasis, and diagnosis in advanced stages of disease are the main reasons for the short survival time and high mortality rate of patients with hepatocellular carcinoma (HCC). Ephrin A4 (EFNA4), the ligand of the EPH family, participates in the development of blood vessels and epithelium by regulating cell migration and rejection. In our study, based on bioinformatics analyses, we found that EFNA4 was highly expressed and led to poor prognosis in patients with HCC. We demonstrated that overexpression of EFNA4 significantly promoted HCC cell proliferation and migration in vivo or in vitro. In addition, knockdown of EFNA4 inhibited the proliferation and migration of HCC cells. Furthermore, EFNA4 was found to directly interact with EPHA2 and promote its phosphorylation at Ser897, followed by recruitment of phosphoinositide-3-kinase regulatory subunit 2 (PIK3R2) and activation of the glycogen synthase kinase-3beta (GSK3β)/β-catenin signaling pathway. Moreover, overexpression of β-catenin further promoted the expression of PIK3R2, which formed a positive feedback loop. The results revealed that abnormal expression of EFNA4 is the main switch of the PIK3R2/GSK3β/β-catenin loop that influenced the proliferation and migration of HCC cells and suggest that EFNA4 is a potential prognostic marker and a prospective therapeutic target in patients with HCC.
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Project description:BackgroundHepatitis B Virus (HBV) contributes to liver carcinogenesis via various epigenetic mechanisms. The newly defined epigenetics, epitranscriptomics regulation, has been reported to involve in multiple cancers including Hepatocellular Carcinoma (HCC). Our previous study found that HBx, HBV encodes X protein, mediated H3K4me3 modification in WDR5-dependent manner to involve in HBV infection and contribute to oncogene expression. AlkB Homolog 5 (ALKBH5), one of epitranscriptomics enzymes, has been identified to be associated with various cancers. However, whether and how ALKBH5 is dysregulated in HBV-related HCC remains unclear yet. This study aims to investigate ALKBH5 function, clinical significance and mechanism in HBV related HCC (HBV-HCC) patients derived from Chinese people.MethodsThe expression pattern of ALKBH5 was evaluated by RT-qPCR, Western blot, data mining and immunohistochemistry in total of 373 HBV-HCC tissues and four HCC cell lines. Cell Counting Kit 8 (CCK8) assay, Transwell and nude mouse model were performed to assess ALKBH5 function by both small interference RNAs and lentiviral particles. The regulation mechanism of ALKBH5 was determined in HBx and WDR5 knockdown cells by CHIP-qPCR. The role of ALKBH5 in HBx mRNA N6-methyladenosine (m6A) modification was further evaluated by MeRIP-qPCR and Actinomycin D inhibitor experiment in HBV-driven cells and HBx overexpression cells.ResultALKBH5 increased in tumor tissues and predicts a poor prognosis of HBV-HCC. Mechanically, the highly expressed ALKBH5 is induced by HBx-mediated H3K4me3 modification of ALKBH5 gene promoter in a WDR5-dependent manner after HBV infection. The increased ALKBH5 protein catalyzes the m6A demethylation of HBx mRNA, thus stabilizing and favoring a higher HBx expression level. Furthermore, there are positive correlations between HBx and ALKBH5 in HBV-HCC tissues, and depletion of ALKBH5 significantly inhibits HBV-driven tumor cells' growth and migration in vitro and in vivo.ConclusionsHBx-ALKBH5 may form a positive-feedback loop to involve in the HBV-induced liver carcinogenesis, and targeting the loop at ALKBH5 may provide a potential way for HBV-HCC treatment.
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Project description:miR-17 family microRNAs (miRNAs) are crucial for embryo development, however, their role in muscle development is still unclear. miR-20a-5p and miR-20b-5p belong to the miR-17 family and are transcribed from the miR-17~92 and miR-106a~363 clusters respectively. In this study, we found that miR-20a-5p and miR-20b-5p promoted myoblast differentiation and repressed myoblast proliferation by directly binding the 3' UTR of E2F transcription factor 1 (E2F1) mRNA. E2F1 is an important transcriptional factor for organism's normal development. Overexpression of E2F1 in myoblasts promoted myoblast proliferation and inhibited myoblast differentiation. Conversely, E2F1 inhibition induced myoblast differentiation and repressed myoblast proliferation. Moreover, E2F1 can bind directly to promoters of the miR-17~92 and miR-106a~363 clusters and activate their transcription, and E2F1 protein expression is correlated with the expression of pri-miR-17~92 and pri-miR-106a~363 during myoblast differentiation. These results suggested an auto-regulatory feedback loop between E2F1 and miR-20a-5p/20b-5p, and indicated that miR-20a-5p, miR-20b-5p and E2F1 are involved in myoblast proliferation and differentiation through the auto-regulation between E2F1 and miR-20a-5p/20b-5p. These findings provide new insight into the mechanism of muscle differentiation, and further shed light on the understanding of muscle development and muscle diseases.
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Project description:Non-small cell lung cancer (NSCLC) is a prevalent subtype of lung cancer, whose mortality is high. Long non-coding RNAs (lncRNAs) have caught rising attentions because of their intricate roles in regulating cancerization and cancer progression. Long intergenic non-protein coding RNA 461 (LINC00461) has recently shown oncogenic potential in several cancers, but the function of LINC00461 in NSCLC remains to be investigated. Our study planned to unveil the regulatory role of LINC00461 in NSCLC. It was validated that LINC00461 was highly expressed in NSCLC tissues and cell lines and exhibited prognostic significance. Furthermore, LINC00461 expression in advanced stage was much higher than in early stage. Loss-of-function experiments suggested that LINC00461 knockdown impaired cell proliferation, migration, and epithelial-to-mesenchymal transition (EMT). Subcellular fractionation revealed the predominant location of LINC00461 in cytoplasm. Mechanistically, LINC00461 up-regulated E2F transcription factor 1 (E2F1) expression through sponging miR-4478. Besides, E2F1 bound to the promoter of LINC00461 to induce its transcription. Finally, rescue experiments verified that LINC00461 aggravated proliferation, migration, and EMT through targeting miR-4478/E2F1 axis. In consequence, the present study illustrated that LINC00461/miR-4478/E2F1 feedback loop promoted NSCLC cell proliferation and migration, providing a new prognostic marker for NSCLC.
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Project description:UNLABELLED:Senescence induction contributes to cancer therapy responses and is crucial for p53-mediated tumor suppression. However, whether p53 inactivation actively suppresses senescence induction has been unclear. Here, we show that E2F1 overexpression, due to p53 or p21 inactivation, promotes expression of human oncoprotein CIP2A, which in turn, by inhibiting PP2A activity, increases stabilizing serine 364 phosphorylation of E2F1. Several lines of evidence show that increased activity of E2F1-CIP2A feedback renders breast cancer cells resistant to senescence induction. Importantly, mammary tumorigenesis is impaired in a CIP2A-deficient mouse model, and CIP2A-deficient tumors display markers of senescence induction. Moreover, high CIP2A expression predicts for poor prognosis in a subgroup of patients with breast cancer treated with senescence-inducing chemotherapy. Together, these results implicate the E2F1-CIP2A feedback loop as a key determinant of breast cancer cell sensitivity to senescence induction. This feedback loop also constitutes a promising prosenescence target for therapy of cancers with an inactivated p53-p21 pathway. SIGNIFICANCE:It has been recently realized that most currently used chemotherapies exert their therapeutic effect at least partly by induction of terminal cell arrest, senescence. However, the mechanisms by which cell-intrinsic senescence sensitivity is determined are poorly understood. Results of this study identify the E2F1-CIP2A positive feedback loop as a key determinant of breast cancer cell sensitivity to senescence and growth arrest induction. Our data also indicate that this newly characterized interplay between 2 frequently overexpressed oncoproteins constitutes a promising prosenescence target for therapy of cancers with inactivated p53 and p21. Finally, these results may also facilitate novel stratification strategies for selection of patients to receive senescence-inducing cancer therapies.
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Project description:Non-small cell lung cancer (NSCLC) is a highly lethal disease worldwide. We found the pseudogene-derived lncRNA PTTG3P is upregulated in NSCLC and associated with larger tumor size, advanced staging, and poor prognosis. This study investigated the oncogenic roles and mechanisms of PTTG3P in NSCLC. We demonstrate that PTTG3P promoted NSCLC cell proliferation, migration, tumorigenesis, and metastasis while inhibiting apoptosis in vitro and in vivo. Mechanistically, PTTG3P formed an RNA-protein complex with ILF3 to maintain MAP2K6 and E2F1 mRNA stability, two oncogenic factors involved in NSCLC progression. RNA-seq revealed MAP2K6 and E2F1 were downregulated upon PTTG3P knockdown. RIP and RNA stability assays showed PTTG3P/ILF3 interaction stabilized MAP2K6 and E2F1 transcripts. Interestingly, E2F1 transcriptionally upregulated PTTG3P by binding its promoter, forming a positive feedback loop. Knockdown of E2F1 or PTTG3P attenuated their mutual regulatory effects on cell growth and migration. Thus, a PTTG3P/ILF3/E2F1 axis enhances oncogene expression to promote NSCLC pathogenesis. Our study reveals PTTG3P exerts oncogenic functions in NSCLC via mRNA stabilization and a feedback loop, highlighting its potential as a prognostic biomarker and therapeutic target.
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Project description:IntroductionSuper-enhancer-associated lncRNAs play important roles in the occurrence and development of malignant tumors, including hepatocellular carcinoma (HCC).ObjectivesThe current work aimed to identify and characterize super-enhancer-associated lncRNAs in the pathogenesis of HCC.MethodsH3K27ac ChIP-seq data from HepG2 cell line and two HCC tissues were used to identify super-enhancer-associated lncRNAs in HCC. JQ-1 treatment and CRISPR-dCas9 system were performed to confirm super-enhancer activity. Quantitative real-time PCR (qPCR), ChIP-qPCR, and dual-luciferase reporter system assay demonstrated the regulation of E2F1 on super-enhancer. Functional loss experiment was used to identify the function of LINC01004.ResultsIn this study, we identified and characterized LINC01004, a novel super-enhancer-associated lncRNA, as a crucial oncogene in HCC. LINC01004 was upregulated in liver cancer tissues and was associated with poor patient prognosis. Moreover, LINC01004 promoted cell proliferation and metastasis of HCC. The binding of E2F1 to the super-enhancer could promote the transcription of LINC01004, while the inhibition of super-enhancer activity decreased LINC01004 expression.ConclusionThis finding might provide mechanistic insights into the molecular mechanisms underlying hepatocarcinogenesis and the biological function of super-enhancer. LINC01004 can serve as a potential therapeutic target for HCC patient.
| S-EPMC9887888 | biostudies-literature
Project description:As patient survival drops precipitously from early-stage cancers to late-stage and metastatic cancers, microRNAs that promote relapse and metastasis can serve as prognostic and predictive markers as well as therapeutic targets for chemoprevention. Here we show that miR-1269a promotes colorectal cancer (CRC) metastasis and forms a positive feedback loop with TGF-? signalling. miR-1269a is upregulated in late-stage CRCs, and long-term monitoring of 100 stage II CRC patients revealed that miR-1269a expression in their surgically removed primary tumours is strongly associated with risk of CRC relapse and metastasis. Consistent with clinical observations, miR-1269a significantly increases the ability of CRC cells to invade and metastasize in vivo. TGF-? activates miR-1269 via Sox4, while miR-1269a enhances TGF-? signalling by targeting Smad7 and HOXD10, hence forming a positive feedback loop. Our findings suggest that miR-1269a is a potential marker to inform adjuvant chemotherapy decisions for CRC patients and a potential therapeutic target to deter metastasis.
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Project description:Epstein-Barr virus (EBV) is considered a ubiquitous herpesvirus with the ability to cause latent infection in humans worldwide. EBV-association is evidently linked to different types of human malignancies, mainly of epithelial and lymphoid origin. Of interest is the EBV nuclear antigen 3C (EBNA3C) which is critical for EBV-mediated immortalization. Recently, EBNA3C was shown to bind the E2F1 transcription regulator. The E2F transcription factors have crucial roles in various cellular functions, including cell cycle, DNA replication, DNA repair, cell mitosis, and cell fate. Specifically, E2F6, one of the unique E2F family members, is known to be a pRb-independent transcription repressor of E2F-target genes. In our current study, we explore the role of EBNA3C in regulating E2F6 activities. We observed that EBNA3C plays an important role in inducing E2F6 expression in LCLs. Our study also shows that EBNA3C physically interacts with E2F6 at its amino and carboxy terminal domains and they form a protein complex in human cells. In addition, EBNA3C stabilizes the E2F6 protein and is co-localized in the nucleus. We also demonstrated that both EBNA3C and E2F6 contribute to reduction in E2F1 transcriptional activity. Moreover, E2F1 forms a protein complex with EBNA3C and E2F6, and EBNA3C competes with E2F1 for E2F6 binding. E2F6 is also recruited by EBNA3C to the E2F1 promoter, which is critical for EBNA3C-mediated cell proliferation. These results demonstrate a critical role for E2F family members in EBV-induced malignancies, and provide new insights for targeting E2F transcription factors in EBV-associated cancers as potential therapeutic intervention strategies.
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