Epigenetics and genetics of hepatoblastoma: Linkage and treatment

Zhu, Liran; Zheng, Wanqun; Gao, Qun; Chen, Tianping; Pan, Zhu-bin; Cui, Wei; Cai, Ming; Fang, Hui

doi:10.3389/fgene.2022.1070971

Cited by 6 publications

(2 citation statements)

References 129 publications

(137 reference statements)

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“…In agreement with these reports, recent studies revealed that the inhibition of methyltransferase activity of G9a/DNMT1 reduces the proliferation of HBL cells and growth of HBL spheroids [17]. The critical role of microRNAs, as well as the role of LncRNAs in the development of HBL, was also recently described in several papers [14,18,19]. An additional epigenetic pathway in hepatoblastoma and in HCC is related to the modification of m6A in mRNAs [20,21].…”

Section: Introductionsupporting

confidence: 61%

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Inhibition of Histone Deacetylase Activity Increases Cisplatin Efficacy to Eliminate Metastatic Cells in Pediatric Liver Cancers

Gulati,

Fleifil,

Jennings

et al. 2024

Cancers

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The pediatric liver cancers, hepatoblastoma and hepatocellular carcinoma, are dangerous cancers which often spread to the lungs. Although treatments with cisplatin significantly improve outcomes, cisplatin may not eliminate metastasis-initiating cells. Our group has recently shown that the metastatic microenvironments of hepatoblastoma contain Cancer Associated Fibroblasts (CAFs) and neuron-like cells, which initiate cancer spread from liver to lungs. In this study, we found that these cells express high levels of HDAC1; therefore, we examined if histone deacetylase inhibition improves cisplatin anti-proliferative effects and reduces the formation of tumor clusters in pediatric liver cancer metastatic microenvironments. Methods: New cell lines were generated from primary hepatoblastoma liver tumors (hbl) and lung metastases (LM) of HBL patients. In addition, cell lines were generated from hepatocellular neoplasm, not otherwise specified (HCN-NOS) tumor samples, and hcc cell lines. Hbl, LM and hcc cells were treated with cisplatin, SAHA or in combination. The effect of these drugs on the number of cells, formation of tumor clusters and HDAC1-Sp5-p21 axis were examined. Results: Both HBL and HCC tissue specimens have increased HDAC1-Sp5 pathway activation, recapitulated in cell lines generated from the tumors. HDAC inhibition with vorinostat (SAHA) increases cisplatin efficacy to eliminate CAFs in hbl and in hcc cell lines. Although the neuron-like cells survive the combined treatments, proliferation was inhibited. Notably, combining SAHA with cisplatin overcame cisplatin resistance in an LM cell line from an aggressive case with multiple metastases. Underlying mechanisms of this enhanced inhibition include suppression of the HDAC1-Sp5 pathway and elevation of an inhibitor of proliferation p21. Similar findings were found with gemcitabine treatments suggesting that elimination of proliferative CAFs cells is a key event in the inhibition of mitotic microenvironment. Conclusions: Our studies demonstrate the synergistic benefits of HDAC inhibition and cisplatin to eliminate metastasis-initiating cells in pediatric liver cancers.

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Section: Introductionsupporting

confidence: 61%

“…Recent studies of HBL have identified epigenetic changes in the levels of DNA methylation, microRNAs, LncRNAs and histone modification [14]. Rivas and colleagues first found that DNA methylation is an essential epigenetic player in HBL [15].…”

Section: Introductionmentioning

confidence: 99%

Inhibition of Histone Deacetylase Activity Increases Cisplatin Efficacy to Eliminate Metastatic Cells in Pediatric Liver Cancers

Gulati,

Fleifil,

Jennings

et al. 2024

Cancers

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First Transcriptome Analysis of Hepatoblastoma in Brazil: Unraveling the Pivotal Role of Noncoding RNAs and Metabolic Pathways

Aguiar,

Rivas,

de Andrade Silva

et al. 2024

Biochem Genet

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Hepatoblastoma, the most common liver tumor in children and exhibited the lowest mutational burden among solid cancers, pointing to chromosomal and epigenetic changes as the main drivers of tumorigenesis. Previous studies explored hepatoblastoma transcriptomes focusing on risk strati cation, but no consensual molecular signature emerged. We performed whole-transcriptome analysis with total RNA sequencing using 14 hepatoblastomas compared with control liver samples. A set of 1,492 differentially expressed genes (DEGs) was detected, 1,031 upregulated and 461 downregulated, comprising 920 protein-coding genes (62%). A strong dysregulation of non-coding RNA genes (ncRNAs) was revealed, mostly upregulated. Among the top 50 genes with the highest expression, 42% of them were ncRNAs, and three (MAGED4, SNO144-16, and RP11-431J24.2) were exclusively expressed by hepatoblastomas. Upregulated biological processes were linked to cell differentiation, communication and signaling pathways, as well as embryonic and developmental processes. Enriched biological processes in downregulated genes included mainly negative regulation of oxidation and metabolism inhibition, affecting amine, nicotinamide, and lipids. An integrative analysis between miRNA-mRNA and protein-protein interaction networks highlighted major biological processes associated with metabolism and oxidation reactions of lipids and carbohydrates, methylation-dependent chromatin silencing, and DNA methylation. Four upregulated miRNAs (miR-186, miR-214, miR-377, and miR-494) were disclosed, potentially targeting more than 10 protein-coding transcripts, which suggested a possible role in their negative regulation. In conclusion, the RNASeq analysis revealed the disruption of metabolic pathways, including lipids, amines, and nicotinamides, and disclosed a robust ncRNA transcriptome perturbation, highlighting a new epigenetic player in the control of hepatoblastoma gene expression, along with DNA methylation. Key MessagesWhole-transcriptome analysis with total RNA sequencing using 14 hepatoblastomas compared with control liver samples. 1,492 differentially expressed genes (DEGs) was detected.1,031 upregulated and 461 downregulated, comprising 920 protein-coding genes (62%).Among the top 50 genes with the highest expression, 42% of them were ncRNAs.RNASeq analysis revealed the disruption of metabolic pathways and disclosed a robust ncRNA transcriptome perturbation.

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