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Epigenetic regulation of the DNMT1/MT1G/KLF4/CA9 axis synergizes the anticancer effects of sorafenib in hepatocellular carcinoma

ABSTRACT: Sorafenib, a multiple-kinase inhibitor, has been widely used as a first-line anticancer drug for advanced hepatocellular carcinoma (HCC). However, the development of drug resistance to sorafenib is frequently observed in clinical applications. Potential non-kinase targets of sorafenib have not been well documented and may provide insights into reversing drug resistance. Herein, we report that sorafenib exerted its anticancer effects by activating metallothionein 1G (MT1G) expression. MT1G served as a novel marker in HCC and correlated well with patient survival. MT1G overexpression suppressed the cellular proliferation, migration, invasion, and tumor formation of HCC, and sensitized cells to sorafenib treatment. However, the disruption of MT1G attenuated sorafenib’s anticancer effects. Mechanistically, sorafenib upregulated MT1G expression via hypomethylation of its promoter region by binding and inhibiting DNA methyltransferase 1 (DNMT1) and increasing its promoter accessibility in HCC cells. The activation of MT1G also inhibited CA9 transcription through the degradation of HIF1a as mediated by KLF4. Our collective data revealed that sorafenib exerted its anticancer effects through epigenetic regulation of the DNMT1/MT1G/KLF4/CA9 axis in HCC, and that the activation of MT1G might constitute a strategy for reversing sorafenib resistance.

ORGANISM(S): Homo sapiens

PROVIDER: GSE192771 | GEO | 2022/04/30

REPOSITORIES: GEO

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Epigenetic regulation of the DNMT1/MT1G/KLF4/CA9 axis synergizes the anticancer effects of sorafenib in hepatocellular carcinoma

Project description:Epigenetic regulation of the DNMT1/MT1G/KLF4/CA9 axis synergizes the anticancer effects of sorafenib in hepatocellular carcinoma

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Expression data from SOX9 knockdown in HCC cells

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Exosomal circRNA-MANBA mediates sorafenib resistance of hepatocellular carcinoma via miR-1290/CD109/p-STAT3 (Ser727) axis

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2019-09-01 | GSE94550 | GEO

cDCBLD2 mediates sorafenib resistance in hepatocellular carcinoma by sponging miR-345-5p binding to the TOP2A coding sequence

Project description:Sorafenib is a first-line chemotherapy drug for treating advanced hepatocellular carcinoma (HCC). However, its therapeutic effect has been seriously affected by the emergence of sorafenib resistance in HCC patients. The underlying mechanism of sorafenib resistance is unclear. Here, we report a circular RNA, cDCBLD2, which plays an important role in sorafenib resistance in HCC. We found that cDCBLD2 was upregulated in sorafenib-resistant (SR) HCC cells, and knocking down cDCBLD2 expression could significantly increase sorafenib-related cytotoxicity. Further evidence showed that cDCBLD2 can bind to microRNA (miR)-345-5p through a competing endogenous RNA mechanism, increase type IIA topoisomerase (TOP2A) mRNA stability through a miRNA sponge mechanism, and reduce the effects of sorafenib treatment on HCC by inhibiting apoptosis. Our findings also suggest that miR-345-5p can negatively regulate TOP2A levels by binding to the coding sequence region of its mRNA. Additionally, targeting cDCBLD2 by injecting a specific small interfering RNA (siRNA) could significantly overcome sorafenib resistance in a patient-derived xenograft (PDX) mouse model of HCC. Taken together, our study provides a proof-of-concept for a potential strategy to overcome sorafenib resistance in HCC patients by targeting cDCBLD2 or TOP2A.

2023-12-11 | GSE240109 | GEO

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Project description:Background & Aims: Existing drug therapies for hepatocellular carcinoma (HCC), including sorafenib, extend patient survival by only three months. We sought to identify novel druggable targets for use in combination with sorafenib to increase its efficacy. Methods: We implemented an in vivo genetic screening paradigm utilizing a library of 43 genes-of-interest expressed in the context of repopulation of the injured livers of Fumarylacetoacetate Hydrolase-deficient (Fah-/-) mice, which led to highly penetrant HCC. We treated mice with vehicle or sorafenib, then determined the genetic drivers of each tumor from the library. Liver X Receptor alpha (LXRalpha) emerged as a potential target. To examine LXRalpha agonism in combination with sorafenib treatment, we added varying concentrations of sorafenib and LXRalpha agonist drugs to HCC cell lines. To elucidate the mechanism of tumor death, we performed transcriptomic analysis. Results: Fah-/- mice injected with the screening library developed HCC tumor clones containing Myc cDNA plus various other cDNAs. Treatment with sorafenib resulted in sorafenib-resistant HCCs that were significantly depleted in Nr1h3 cDNA, encoding LXRalpha, suggesting that LXRalpha activation is incompatible with tumor growth in the presence of sorafenib treatment in vivo. Combination treatment using sorafenib and LXR agonist drugs in multiple HCC cell lines led to enhanced cell death as compared to monotherapy, due to reduced expression of cell cycle regulators and increased expression of genes associated with apoptosis. Combination therapy also enhanced cell death in a sorafenib-resistant primary human HCC cell line. Conclusions: We have completed a novel drug resistance screen in vivo, and identified that LXR agonism potentiates the efficacy of sorafenib in treating HCC.

2020-05-29 | GSE151412 | GEO

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