Dataset Information

Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression.

ABSTRACT: The WD-repeat (WDR) family affects carcinogenesis, but its role in the immune microenvironment is poorly characterized. Although functional loss or gain of WDR6 does not markedly change in vitro proliferative and invasive capacity of HCC cells, its deficiency in hepa1-6 cells drastically inhibits the growth and lung metastasis of orthotopically implanted tumors in immune-competent C57BL/6J mice. Mechanistically, WDR6 targets tumor suppressor UVRAG to the CUL4A-DDB1-ROC1 E3 ubiquitin ligase complex through a unique WDxR motif and promotes its degradation. This upregulates chromatin accessibility at the TNFα locus by blocking autophagic degradation of p65, elevates intratumoral myeloid-derived suppressor cell (MDSC) number, and reduces CD8⁺ T cell infiltration, thereby promoting HCC progression. These immunosuppressive effects are reversed by TNFα blockade. TNFα recruits NF-κB to activate the transcription of WDR6, establishing a WDR6-TNFα loop. Clinically, the WDR6/UVRAG/NF-κB pathway is hyperactivated in HCC, predicting a poor prognosis. Importantly, a WDxR-like peptide disrupts the WDR6/UVRAG complex and enhances the efficiency of anti-PD-L1 against HCC with WDR6 dysregulation.

SUBMITTER: Zhang H

PROVIDER: S-EPMC10165360 | biostudies-literature | 2023 May

REPOSITORIES: biostudies-literature

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Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression.

Zhang Heng H Chen Gang G Feng Xing X Song Huiwen H Meng Lingbing L Fu Yao Y Yang Jun J Fan Zhiwen Z Ding Youxiang Y Du Zhijie Z Wang Jianchao J Yang Li L Zhang Jun J Sun Lixia L Liu Zhigang Z Zhang Zhiyong Z Li Quanhai Q Fan Xiangshan X

EMBO molecular medicine 20230322 5

The WD-repeat (WDR) family affects carcinogenesis, but its role in the immune microenvironment is poorly characterized. Although functional loss or gain of WDR6 does not markedly change in vitro proliferative and invasive capacity of HCC cells, its deficiency in hepa1-6 cells drastically inhibits the growth and lung metastasis of orthotopically implanted tumors in immune-competent C57BL/6J mice. Mechanistically, WDR6 targets tumor suppressor UVRAG to the CUL4A-DDB1-ROC1 E3 ubiquitin ligase compl ...[more]

PMID: 36947051

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Project description:BackgroundProtein arginine methyltransferase (PRMT) family members have important roles in cancer processes. However, its functions in the regulation of cancer immunotherapy of hepatocellular carcinoma (HCC) are incompletely understood. This study aimed to investigate the roles of PRMT1 in HCC.MethodsSingle-cell RNA sequencing (scRNA-seq) and clinicopathological data were obtained and used to explore the diagnostic and prognostic value, cellular functions and roles in immune microenvironment regulation of PRMT1 in HCC. The functions of PRMT1 were explored using Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO), as well as gene set enrichment analysis (GSEA). TIMER and CIBERSORT were used to analyze the relationships between PRMT1 expression and immune cell infiltration. The STRING database was used to construct a protein-protein interaction (PPI) network.ResultsPRMT1 was aberrantly expressed in HCC, which high expression was associated with tumor progression, worse overall survival (OS) and disease-free survival (DFS) of patients with HCC. PRMT1 was also associated with immune cell infiltration. Moreover, it was specifically expressed in immune cells, including exhausted CD8 T cells, B cells, and mono/macro cells in patients with immunotherapy. The expression of immune checkpoints was significantly increased in the high-PRMT1 expression groups of HCC patients. Regarding biological mechanisms, cell viability, migration and invasion, and the expression of genes related to fatty acid metabolism were suppressed in PRMT1 knockdown HCC cells. Moreover, genes co-expressed with PRMT1 were involved in the fatty acid metabolic process and enriched in fatty and drug-induced liver disease.ConclusionTaken together, these results indicate that PRMT1 might exert its oncogenic effects via immune microenvironment regulation and fatty acid metabolism in HCC. Our finding will provide a foundation for further studies and indicate a potential clinical therapeutic target for liver cancer.

Project description:BackgroundSchisandrin B (Sch. B) performs various pharmacological properties, including anticancer activities. However, the pharmacological mechanisms of Sch. B in hepatocellular carcinoma (HCC) are not fully elucidated. We investigated the impact and mechanism on progression in HCC, and to provide new experimental evidence for HCC treatment.MethodsTo determine the inhibitory effect of Sch. B on HCC in vivo, 32 Balb/c nude mice were used to prepare the tumor-bearing mice model by subcutaneously inoculating HCC cells (Huh-7). As tumor volume grew to 100 mm3, mice were randomly divided into Saline (control group), 100 mg/kg Sch. B group (Sch. B-L), 200 mg/kg Sch. B group (Sch. B-M), and 400 mg/kg Sch. B group (Sch. B-H) (n=8). Saline or different concentration Sch. B was used to treat mice via gavage administration for 21 days. After mice were euthanized, tumor weight and volume were evaluated. Cell apoptosis was detected by TUNEL. Ki-67 and PCNA were detected by immunohistochemical staining. The RhoA and Rho-associated protein kinase 1 (ROCK1) were determined by western blot. In vitro experiment, Huh-7 cell were treated by Sch. B at 40, 30, 20, 10, 5, 1, and 0 µM to detect cell proliferation by Cell Counting Kit-8 (CCK-8). Huh-7 cells were divided as a control group, Sch. B group, and Sch. B + RhoA overexpression (Sch. B + RhoA) group. RhoA and ROCK1 were examined. The colony formation assay and flow cytometry were used to detect cell proliferation and apoptosis. The wound healing and Transwell assays were used for cell metastasis detection.ResultsOur results showed 100, 200 and 400 mg/kg Sch. B significantly reduced tumor weight and volume. And 200 and 400 mg/kg Sch. B increased apoptosis, and reduced Ki-67 and PCNA levels, inhibited the RhoA and ROCK1 in vivo (P<0.05). In vitro experiment, Sch. B inhibited Huh-7 cell proliferation at concentration more than 10 μM (P<0.05). Sch. B decreased cell duplication, promoted apoptosis and blocked migration and invasion of Huh-7 (P<0.05). Sch. B inhibited RhoA and ROCK1 level as compared with control group (P<0.05). RhoA overexpression reversed the effect of Sch. B (P<0.05).ConclusionsSch. B inhibits Huh-7 cells progression via RhoA/ROCK1 pathway. The results provide new evidence for the clinical treatment of HCC.

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Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression.

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Targeting WDxR motif reprograms immune microenvironment and inhibits hepatocellular carcinoma progression.

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