High mobility group AT-hook 1 (HMGA1) is an important positive regulator of hepatitis B virus (HBV) that is reciprocally upregulated by HBV X protein

Shen, Zhongliang; Wu, Jingwen; Gao, Zixiang; Zhang, Shenyan; Chen, Jingwen; He, Jingjing; Guo, Yifei; Deng, Qiang; Xie, Youhua; Jing, Liu; Zhang, Jiming

doi:10.1093/nar/gkac070

Cited by 21 publications

(9 citation statements)

References 51 publications

(70 reference statements)

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“…According to the study by Shen et al, HMGA1 protein could positively regulate HBV transcription via recruiting transcription factors forkhead box O3alpha (FOXO3α) and peroxisome proliferator-activated receptor-γ coactivator-1α (PGC1α). On the other hand, HMGA1-targeted treatment facilitates HBV clearance ( Shen et al, 2022 ). Similarly, Andreozzi et al observed monotonically increased HMGA1 expression in tissues from normal liver to cirrhotic transformation, to primary HCC and to disease metastasis.…”

Section: Discussionmentioning

confidence: 99%

A novel transcription factor-based signature to predict prognosis and therapeutic response of hepatocellular carcinoma

Yang

Ye²,

Zhang³

et al. 2023

Front. Genet.

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Background: Hepatocellular carcinoma (HCC) is one of the most common aggressive malignancies with increasing incidence worldwide. The oncogenic roles of transcription factors (TFs) were increasingly recognized in various cancers. This study aimed to develop a predicting signature based on TFs for the prognosis and treatment of HCC.Methods: Differentially expressed TFs were screened from data in the TCGA-LIHC and ICGC-LIRI-JP cohorts. Univariate and multivariate Cox regression analyses were applied to establish a TF-based prognostic signature. The receiver operating characteristic (ROC) curve was used to assess the predictive efficacy of the signature. Subsequently, correlations of the risk model with clinical features and treatment response in HCC were also analyzed. The TF target genes underwent Gene Ontology (GO) function and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analyses, followed by protein-protein-interaction (PPI) analysis.Results: A total of 25 differentially expressed TFs were screened, 16 of which were related to the prognosis of HCC in the TCGA-LIHC cohort. A 2-TF risk signature, comprising high mobility group AT-hook protein 1 (HMGA1) and MAF BZIP transcription factor G (MAFG), was constructed and validated to negatively related to the overall survival (OS) of HCC. The ROC curve showed good predictive efficiencies of the risk score regarding 1-year, 2-year and 3-year OS (mostly AUC >0.60). Additionally, the risk score independently predicted OS for HCC patients both in the training cohort of TCGA-LIHC dataset (HR = 2.498, p = 0.007) and in the testing cohort of ICGC-LIRI-JP dataset (HR = 5.411, p < 0.001). The risk score was also positively correlated to progressive characteristics regarding tumor grade, TNM stage and tumor invasion. Patients with a high-risk score were more resistant to transarterial chemoembolization (TACE) treatment and agents of lapatinib and erlotinib, but sensitive to chemotherapeutics. Further enrichment and PPI analyses demonstrated that the 2-TF signature distinguished tumors into 2 clusters with proliferative and metabolic features, with the hub genes belonging to the former cluster.Conclusion: Our study identified a 2-TF prognostic signature that indicated tumor heterogeneity with different clinical features and treatment preference, which help optimal therapeutic strategy and improved survival for HCC patients.

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Section: Discussionmentioning

confidence: 99%

A novel transcription factor-based signature to predict prognosis and therapeutic response of hepatocellular carcinoma

Yang

Ye²,

Zhang³

et al. 2023

Front. Genet.

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“…On the other end of the functional spectrum, many VIPs do not have any immune function and are in fact proviral factors that assist viruses when the latter hijack their molecular functions to complete multiple steps of their replication cycle (Table S1). For example, viruses subvert host transcription regulators to activate the expression of their own viral genes during infection (Chau et al, 2008; Scoggin et al, 2001; Shen et al, 2022). We predict that immune antiviral and non-immune proviral VIPs should have experienced different patterns of protein stability evolution.…”

Section: Resultsmentioning

confidence: 99%

Stability evolution as a major mechanism of human protein adaptation in response to viruses

Murga-Moreno

Enard

2022

Preprint

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Pathogens were a major driver of genetic adaptation during human evolution. Viruses in particular were a dominant driver of adaptation in the thousands of proteins that physically interact with viruses (VIPs for Virus-Interacting Proteins). This however poses a conundrum. The best understood cases of virus-driven adaptation in specialized immune antiviral factors or in host viral receptors are numerically vastly insufficient to explain abundant adaptations in VIPs. What adaptive mechanisms can then at least partly close this gap? VIPs tend to be broadly conserved proteins with conserved host native molecular functions. Because many amino acid changes in a protein can alter its stability --the balance between the folded and unfolded forms of a protein-- without destroying conserved native activities, here we ask if stability evolution was an important mechanism of virus-driven human protein adaptation. Using predictions of protein stability changes based on Alphafold 2 structures and validated by multiple lines of evidence, we find that amino acid changes that altered stability experienced highly elevated adaptative evolution in VIPs, compared to changes with a weaker impact on stability. We further find that RNA viruses, rather DNA viruses, predominantly drove strong adaptation through stability changes in VIPs. We also observe that stability in immune antiviral VIPs preferentially evolved under directional selection. Conversely, stability in proviral VIPs needed by viruses evolved under compensatory evolution following viral epidemics. Together, these results suggest that stability evolution, and thus functional host protein abundance evolution, was a prominent mechanism of host protein adaptation during viral epidemics.

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“…A previous study described the extraction of HBV cccDNA [50][51][52]. Cells were lysed in lysis buffer containing 50 mM Tris-HCl, pH 7.4, 1 mM EDTA, and 1% NP-40 supplemented with proteinase inhibitor cocktail (Topscience, China) for 10 min.…”

Section: Hbv Cccdna Quantitationmentioning

confidence: 99%

Phosphorylation of UHRF2 affects malignant phenotypes of HCC and HBV replication by blocking DHX9 ubiquitylation

Zhang

Liu

et al. 2023

Cell Death Discov.

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Hepatitis B virus (HBV) infection is one of main contributors to poor prognosis and rapid progression of hepatocellular cancer (HCC). We previously identified the important role of the phosphorylation of ubiquitin-like with PHD and ring finger domains (UHRF2) in HBV-associated HCC. In this study we identify upregulated UHRF2 protein levels in HBV-associated HCC cells and tissues. UHRF2 overexpression promotes the viability, proliferation, migration and invasiveness of HBV-positive HCC cell lines, and enhances HBV DNA replication. To obtain a comprehensive understanding of the interaction networks of UHRF2 and their underlying mechanism, this study suggests that UHRF2 facilitates the ubiquitin-proteasome-mediated proteolysis of DExD/H (Asp-Glu-Ala-His) -box helicase enzyme 9 (DHX9). However, phosphorylation of UHRF2 by HBx at S643 inhibits E3 ubiquitin ligase activity of UHRF2 and improves DHX9 protein stability. Furthermore, results suggest that HBx promotes phosphorylation of UHRF2 by the ETS1-CDK2 axis through the downregulation of miR-222-3p in HBV-associated HCC specimens and cells. Our findings suggest that HBx-induced phosphorylation of UHRF2 S643 acts as a “switch” in HBV-associated HCC oncogenesis, activating the positive feedback between phosphorylated UHRF2 and HBV, provide evidence that UHRF2 is a new regulator and a potential prognostic indicator of poor prognosis for HBV-associated HCC.

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High mobility group AT-hook 1 (HMGA1) is an important positive regulator of hepatitis B virus (HBV) that is reciprocally upregulated by HBV X protein

Cited by 21 publications

References 51 publications

A novel transcription factor-based signature to predict prognosis and therapeutic response of hepatocellular carcinoma

A novel transcription factor-based signature to predict prognosis and therapeutic response of hepatocellular carcinoma

Stability evolution as a major mechanism of human protein adaptation in response to viruses

Phosphorylation of UHRF2 affects malignant phenotypes of HCC and HBV replication by blocking DHX9 ubiquitylation

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