Dataset Information

Inhibition of HMGB1 Suppresses Hepatocellular Carcinoma Progression via HIPK2-Mediated Autophagic Degradation of ZEB1.

ABSTRACT: Autophagy is a conserved catabolic process maintaining cellular homeostasis and reportedly plays a critical role in tumor progression. Accumulating data show that autophagic activity is inhibited in hepatocellular carcinoma. However, the underlying molecular basis of impaired autophagy in HCC remains unclear. In this study, we revealed that autophagic activity was suppressed by HMGB1 in a HIPK2-dependent way. Targeting HMGB1 could inhibit the degradation of HIPK2, as a result of which, autophagic degradation of ZEB1 was enhanced by reprogramming glucose metabolism/AMPK/mTOR axis. Moreover, we demonstrated that selectively degradation of ZEB1 was responsible for HCC growth inhibition in HMGB1 deficient cells. Lastly, we found the combination therapy of HMGB1 inhibitor and rapamycin achieved a better anti-HCC effect. These results demonstrate that impaired autophagy is controlled by HMGB1 and targeting HMGB1 could suppress HCC progression via HIPK2-mediated autophagic degradation of ZEB1.

SUBMITTER: Zhu W

PROVIDER: S-EPMC7969871 | biostudies-literature | 2021

REPOSITORIES: biostudies-literature

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Inhibition of HMGB1 Suppresses Hepatocellular Carcinoma Progression <i>via</i> HIPK2-Mediated Autophagic Degradation of ZEB1.

Zhu Wei W Li Jun J Zhang Yuheng Y Zhu Zhengyi Z Liu Hanyi H Lin Yunzhen Y Hu Anyin A Zhou Jingchao J Ren Haozhen H Shi Xiaolei X

Frontiers in oncology 20210304

Autophagy is a conserved catabolic process maintaining cellular homeostasis and reportedly plays a critical role in tumor progression. Accumulating data show that autophagic activity is inhibited in hepatocellular carcinoma. However, the underlying molecular basis of impaired autophagy in HCC remains unclear. In this study, we revealed that autophagic activity was suppressed by HMGB1 in a HIPK2-dependent way. Targeting HMGB1 could inhibit the degradation of HIPK2, as a result of which, autophagi ...[more]

PMID: 33747917

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Project description:BackgroundHepatocellular carcinoma (HCC) is the third cause of cancer death in the world, and few molecularly targeted anticancer therapies have been developed to treat it. The E3 ubiquitin ligase RNF152 has been reported to regulate the activity of the mechanistic target of rapamycin complex 1 (mTORC1), induce autophagy and apoptosis. However, the relationship between RNF152 and HCC is unclear.MethodsTranscriptome RNA-sequencing data of HCC samples and normal tissues were used to detect the mRNA expression of RNF152. Luciferase reporter and chromatin immunoprecipitation (ChIP) assays were used to determine the transcriptional regulation of RNF152 in HCC by FoxO1. RNAi, cell proliferation, colony formation and transwell assays were used to determine the in vitro functions of RNF152. Mouse xenograft models were used to study the in vivo effects of RNF152. The immunoprecipitation assay was used to determine the interaction between RNF152 and TSPAN12. The in vivo ubiquitination assay was performed to determine the regulation of TSPAN12 by RNF152.ResultsWe found that RNF152 is significantly down-regulated in clinic HCC samples, and its down-regulation is associated with pool overall survival (OS), progression-free survival (PFS) and disease-specific survival (DSS) in HCC patients. The transcription factor FoxO1 was significantly positively correlated RNF152 expression in HCC tissues. FoxO1 recognizes a classic insulin response element (IRE) on the RNF152 promoter to regulate its expression in HCC. RNF152 suppressed HCC cell proliferation, clonogenic survival, invasion in vitro, and tumorigenesis in vivo. Mechanistically, RNF152 interacted with TSPAN12 and targeted it for ubiquitination and proteasomal degradation, thereby inhibiting TSPAN12-dependent CXCL6 expression and HCC progression.ConclusionCollectively, our data revealed a tumor suppressor role of RNF152 and a connection between RNF152 and FoxO1 in HCC. Our results support an important role of the FoxO1-RNF152-TSPAN12 axis in the development of HCC. Therapeutic targeting this axis may be an effective means of treating HCC.

Project description:BackgroundHepatocellular carcinoma (HCC) has a hidden onset and high malignancy. Its high metastasis, high recurrence, and short survival time have always been a difficult and hot spot in clinical practice. Our previous study revealed that myc-associated zinc finger protein (MAZ) is highly upregulated in HCC tissues and may promote the proliferation and metastasis of HCC cells by inducing the epithelial-mesenchymal transformation (EMT) process. However, the specific regulatory mechanism by which MAZ functions as an oncogene in HCC has still not been fully elucidated.MethodsImmunohistochemical staining and bioinformatics analyses were conducted to measure the expression of MAZ, key m6A enzymes, and ZEB1 in HCC tissues. RNA sequencing (RNA-seq) of MAZ knockdown HCC cells and human mRNA m6A sequencing (m6A-seq) of HCC tissues were intersected to screen the downstream targets for both MAZ and m6A methylation. The correlations between MAZ and its targets were analyzed by dual-luciferase assays and cell rescue experiments.ResultsHere, we report for the first time that MAZ is involved in m6A methylation of HCC by targeting the transcriptional regulation of key m6A enzymes. MAZ expression was significantly correlated with the expression of key m6A enzymes in HCC tissues and cell lines. Moreover, MAZ could bind to the promoters of key m6A enzymes, and multivariate Cox regression analysis suggested that MAZ and METTL3 expression were independent risk factors for the survival of HCC patients. Through RNA-seq and m6A-seq, we screened out EMT regulators ZEB1 and TRIM50 as the downstream targets for both MAZ and m6A methylation. Mechanistically, m6A sites with high confidence in ZEB1 and TRIM50 mRNA were identified by SRAMP, and there were significant relationships between ZEB1 and METTL3 in HCC tissues and cells. A nomogram model was established to better display the combined effect of MAZ, METTL3, and ZEB1 on HCC prognosis.ConclusionsOur study revealed a promising clinical application of MAZ, METTL3, and ZEB1 in HCC prognosis, further suggesting that MAZ can be used as a potential molecular biomarker for HCC diagnosis and prognosis.

Dataset Information

Inhibition of HMGB1 Suppresses Hepatocellular Carcinoma Progression via HIPK2-Mediated Autophagic Degradation of ZEB1.

Publications

Inhibition of HMGB1 Suppresses Hepatocellular Carcinoma Progression <i>via</i> HIPK2-Mediated Autophagic Degradation of ZEB1.

Similar Datasets

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