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Targeting VRK2 Enhances the Efficacy of Anti-PD-1 Therapy in Hepatocellular Carcinoma by Reducing Direct Phosphorylation and Stability of MYC，CUT-TAG sequencing for MYC in hepatocellular carcinoma cells

ABSTRACT: VRK2–MYC axis, a transcription-dependent regulatory axis, could be a prognostic indicator and potential therapeutic target in liver cancer.

ORGANISM(S): Homo sapiens

PROVIDER: GSE277990 | GEO | 2025/05/22

REPOSITORIES: GEO

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Targeting VRK2 Enhances the Efficacy of Anti-PD-1 Therapy in Hepatocellular Carcinoma by Reducing Direct Phosphorylation and Stability of MYC，CUT-TAG sequencing for MYC in hepatocellular carcinoma cells [CUT&Tag]

Project description:VRK2–MYC axis, a transcription-dependent regulatory axis, could be a prognostic indicator and potential therapeutic target in liver cancer.

2025-07-08 | GSE301942 | GEO

Targeting VRK2 Enhances the Efficacy of Anti-PD-1 Therapy in Hepatocellular Carcinoma by Reducing Direct Phosphorylation and Stability of MYC: CUT-TAG sequencing for MYC in hepatocellular carcinoma cells

Project description:VRK2–MYC axis, a transcription-dependent regulatory axis, could be a prognostic indicator and potential therapeutic target in liver cancer.

2025-05-22 | GSE278073 | GEO

Project description:Targeting VRK2 Enhances the Efficacy of Anti-PD-1 Therapy in Hepatocellular Carcinoma by Reducing Direct Phosphorylation and Stability of MYC，CUT-TAG sequencing for MYC in hepatocellular carcinoma cells [CUT&Tag]

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Project description:Targeting VRK2 Enhances the Efficacy of Anti-PD-1 Therapy in Hepatocellular Carcinoma by Reducing Direct Phosphorylation and Stability of MYC: CUT-TAG sequencing for MYC in hepatocellular carcinoma cells

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AGO2 Mediates <i>MYC</i> mRNA Stability in Hepatocellular Carcinoma.

Project description:Deregulated RNA-binding proteins (RBP), such as Argonaute 2 (AGO2), mediate tumor-promoting transcriptomic changes during carcinogenesis, including hepatocellular carcinoma (HCC). While AGO2 is well characterized as a member of the RNA-induced silencing complex (RISC), which represses gene expression through miRNAs, its role as a bona fide RBP remains unclear. In this study, we investigated AGO2's role as an RBP that regulates the MYC transcript to promote HCC. Using mRNA and miRNA arrays from patients with HCC, we demonstrate that HCCs with elevated AGO2 levels are more likely to have the mRNA transcriptome deregulated and are associated with poor survival. Moreover, AGO2 overexpression stabilizes the MYC transcript independent of miRNAs. These observations provide a novel mechanism of gene regulation by AGO2 and provide further insights into the potential functions of AGO2 as an RBP in addition to RISC. IMPLICATIONS: Authors demonstrate that the RBP Argonaute 2 stabilizes the MYC transcript to promote HCC.

| S-EPMC7127970 | biostudies-literature

ACSL4 promotes hepatocellular carcinoma progression via c-Myc stability mediated by ERK/FBW7/c-Myc axis.

Project description:Hepatocellular carcinoma (HCC) is a highly heterogeneous, multigene-driven malignant tumor. Long chain acyl-CoA synthetase 4 (ACSL4), an enzyme has pivotal roles in arachidonic acid (AA) metabolism. However, its function and the underlying molecular mechanisms in HCC are still not fully elucidated. Here, we identified ACSL4 as a novel marker for AFP high subtype HCC through transcriptome profiling. ACSL4 was frequently upregulated in HCC samples and associated with poor prognosis. Functionally, ACSL4 knockdown resulted in decreased cell growth, whereas ectopic ACSL4 expression facilitated tumor formation in vitro and in vivo. Mechanistically, ACSL4 stabilized the oncoprotein c-Myc through ubiquitin-proteasome system in an ERK/FBW7-dependent manner. Cell growth ability mediated by ACSL4 elevation was partly attenuated by c-Myc depletion using siRNA or its inhibitor 10058-F4. In contrast, the effects of ACSL4 silencing were partially reversed by c-Myc overexpression via FBW7 knockdown. Clinically, ACSL4 expression was positively correlated with c-Myc in HCC. In conclusion, ACSL4 is a novel marker for AFP high subtype HCC. Our data uncovered a new mechanism by which ACSL4 promotes HCC progression via c-Myc stability mediated by ERK/FBW7/c-Myc axis and could be a valuable prognostic biomarker and a potential therapeutic target in HCC.

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MYC phosphorylation, activation, and tumorigenic potential in hepatocellular carcinoma are regulated by HMG-CoA reductase.

Project description:MYC is a potential target for many cancers but is not amenable to existing pharmacologic approaches. Inhibition of 3-hydroxy-3-methylglutaryl-coenzyme A reductase (HMG-CoA reductase) by statins has shown potential efficacy against a number of cancers. Here, we show that inhibition of HMG-CoA reductase by atorvastatin (AT) blocks both MYC phosphorylation and activation, suppressing tumor initiation and growth in vivo in a transgenic model of MYC-induced hepatocellular carcinoma (HCC) as well as in human HCC-derived cell lines. To confirm specificity, we show that the antitumor effects of AT are blocked by cotreatment with the HMG-CoA reductase product mevalonate. Moreover, by using a novel molecular imaging sensor, we confirm that inhibition of HMG-CoA reductase blocks MYC phosphorylation in vivo. Importantly, the introduction of phosphorylation mutants of MYC at Ser62 or Thr58 into tumors blocks their sensitivity to inhibition of HMG-CoA reductase. Finally, we show that inhibition of HMG-CoA reductase suppresses MYC phosphorylation through Rac GTPase. Therefore, HMG-CoA reductase is a critical regulator of MYC phosphorylation, activation, and tumorigenic properties. The inhibition of HMG-CoA reductase may be a useful target for the treatment of MYC-associated HCC as well as other tumors.

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Focal adhesion kinase activation limits efficacy of Dasatinib in c-Myc driven hepatocellular carcinoma.

Project description:Hepatocellular carcinoma (HCC) is a deadly malignancy with limited treatment options. Recently, it was found that Dasatinib treatment led to synthetic lethality in c-Myc high-expressing human cancer cells due to inhibition of p-Lyn. Overexpression of c-Myc is frequently seen in human HCC. We investigated the sensitivity to Dasatinib in vitro using HCC cell lines and in vivo using c-Myc mouse HCC model. We found that HCC cell line responsiveness to Dasatinib varied significantly. However, there was no correlation between c-Myc expression and IC50 to Dasatinib. In c-Myc-induced HCC in mice, tumors continued to grow despite Dasatinib treatment, although the eventual tumor burden was lower in Dasatinib treatment cohort. Molecular analyses revealed that Dasatinib was effective in inhibiting p-Src, but not p-Lyn, in HCC. Importantly, we found that in HCC cell lines as well as c-Myc mouse HCC, Dasatinib treatment induced up regulation of activated/phosphorylated (p)-focal adhesion kinase(FAK). Concomitant treatment of HCC cell lines with Dasatinib and FAK inhibitor prevented Dasatinib-induced FAK activation, leading to stronger growth restraint. Altogether, our results suggest that Dasatinib may have limited efficacy as single agent for HCC treatment. Combined treatment with Dasatinib with FAK inhibitor might represent a novel therapeutic approach against HCC.

| S-EPMC6308083 | biostudies-literature

The PKCα/ZFP64/CSF1 Axis restricts Tumor Response to Anti-PD1 by driving Macrophage M2 Polarization in Hepatocellular Carcinoma

Project description:Despite remarkable achievements, majority of hepatocellular carcinoma (HCC) patients fail to respond to anti-PD1 therapy. Here, we showed that ZFP64 was frequently upregulated in HCC tissues of anti-PD1 resistance patients. Elevated ZFP64 levels triggered tumor progression and induced an immunosuppressive microenvironment. Mechanistically, ZFP64 transcriptionally activated colony-stimulating factor 1 (CSF1) by directly binding to its promoter, and secreted CSF1 driving the shift of macrophages into an alternatively activated phenotype. Importantly, the PKCα was revealed to phosphorylate ZFP64 at S226, resulting in its nuclear translocation to transcribe the CSF1 gene. Particularly, we proposed firstly that the PKCα/ZFP64/CSF1 axis was a critical pathway in fostering immune evasion and anti-PD1 tolerance and inhibiting this axis with lenvatinib or Gö6976 surmounted the anti-PD1 resistance in HCC. Our study indicates that the ZFP64 is an emerging indicator in predicting anti-PD1 efficacy, and reveals the PKCα/ZFP64/CSF1 axis is a suitable target for anti-PD1 combination therapy in HCC.

2024-08-04 | GSE181436 | GEO

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