Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

Fernández‐Barrena, Maite G.; Arechederra, María; Colyn, Leticia; Berasain, Carmen; Avila, Matı́as A.

doi:10.1016/j.jhepr.2020.100167

Cited by 79 publications

(77 citation statements)

References 176 publications

(287 reference statements)

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“…Together with the genetic landscape of mutations, multiple works have linked different changes in gene expression involved in the pathogenesis and progression of CLD with the rewiring of the epigenomic landscape [ 5 , 6 , 36 ] ( Figure 1 ). Furthermore, multiple observations demonstrate the existence of an interplay between genetic and epigenetic alterations in liver cancer.…”

Section: Epigenetic Reprogramming In Liver Disease: Changes In Epimentioning

confidence: 99%

“…Epigenetic aberrations contribute to the pathogenesis and progression of chronic liver disease [ 5 , 65 ], and changes in DNA methylation have been described at different stages, including hepatitis, fibrosis, and cirrhosis [ 56 , 57 , 59 ]. Importantly, the identification of stage-specific changes in ctDNA would facilitate the monitoring of disease progression and the early diagnosis of tumors.…”

Section: Epigenetic Biomarkers In Liquid Biopsy: Methylated Ctdna mentioning

confidence: 99%

“…Indeed, over the last years DNA hypomethylating agents and histone deacetylase inhibitors (HDACi) have been approved or are being tested for the treatment of hematologic malignancies and solid tumors [ 4 , 70 , 120 , 121 ]. Moreover, recent results have demonstrated that the targeting of epigenetic writers (DNMTs and histone methyltransferases, HMTs), readers (BRDs), and erasers (HDACs and lysine demethylases, KDMs) can synergize with immunotherapy, increasing the immune recognition of tumor cells [ 5 , 122 , 123 , 124 ].…”

Section: Harnessing Epigenetic Alterations For Therapymentioning

confidence: 99%

“…Epigenetic regulation of chromatin includes DNA methylation, nucleosome histone variants, post-translational histone modifications, and non-coding RNAs (ncRNAs) [ 1 ]. This epigenetic information is maintained through the coordinated activity of a plethora of epigenetic factors that modulate nucleosome structure and positioning (remodelers), establish epigenetic marks in DNA and histones (writers), recognize and interpret the marks (readers), and remove these marks (erasers) [ 3 , 4 , 5 , 6 ].…”

Section: Introductionmentioning

confidence: 99%

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Epigenetic Biomarkers for the Diagnosis and Treatment of Liver Disease

Arechederra

Recalde

Gárate-Rascón

et al. 2021

Cancers

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Research in the last decades has demonstrated the relevance of epigenetics in controlling gene expression to maintain cell homeostasis, and the important role played by epigenome alterations in disease development. Moreover, the reversibility of epigenetic marks can be harnessed as a therapeutic strategy, and epigenetic marks can be used as diagnosis biomarkers. Epigenetic alterations in DNA methylation, histone post-translational modifications (PTMs), and non-coding RNA (ncRNA) expression have been associated with the process of hepatocarcinogenesis. Here, we summarize epigenetic alterations involved in the pathogenesis of chronic liver disease (CLD), particularly focusing on DNA methylation. We also discuss their utility as epigenetic biomarkers in liquid biopsy for the diagnosis and prognosis of hepatocellular carcinoma (HCC). Finally, we discuss the potential of epigenetic therapeutic strategies for HCC treatment.

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Section: Epigenetic Reprogramming In Liver Disease: Changes In Epimentioning

confidence: 99%

Section: Epigenetic Biomarkers In Liquid Biopsy: Methylated Ctdna mentioning

confidence: 99%

Section: Harnessing Epigenetic Alterations For Therapymentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

See 2 more Smart Citations

Epigenetic Biomarkers for the Diagnosis and Treatment of Liver Disease

Arechederra

Recalde

Gárate-Rascón

et al. 2021

Cancers

Self Cite

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“…Epigenetic regulation in tumor cells is extensively studied and plays critical roles in HCC development (24)(25)(26). Emerging evidence demonstrates that epigenetic alterations in TME also contribute to the initiation and progression of HCC (27)(28)(29)(30)(31)(32)(33). As the epigenetic regulation of MSCs, MDSCs, and ECs in HCC remain poorly defined, this review will focus on the epigenetics of HSCs, TAMs, and the ECM ( Table 1).…”

Section: Introductionmentioning

confidence: 99%

The Epigenetic Regulation of Microenvironment in Hepatocellular Carcinoma

2021

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Hepatocellular carcinoma (HCC) is a highly lethal and complex malignancy strongly influenced by the surrounding tumor microenvironment. The HCC microenvironment comprises hepatic stellate cells (HSCs), tumor-associated macrophages (TAMs), stromal and endothelial cells, and the underlying extracellular matrix (ECM). Emerging evidence demonstrates that epigenetic regulation plays a crucial role in altering numerous components of the HCC tumor microenvironment. In this review, we summarize the current understanding of the mechanisms of epigenetic regulation of the microenvironment in HCC. We review recent studies demonstrating how specific epigenetic mechanisms (DNA methylation, histone regulation, and non-coding RNAs mediated regulation) in HSCs, TAMs, and ECM, and how they contribute to HCC development, so as to gain new insights into the treatment of HCC via regulating epigenetic regulation in the tumor microenvironment.

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TACE inhibition: a promising therapeutic intervention against AATF‐mediated steatohepatitis to hepatocarcinogenesis

Srinivas,

Suresh,

Vishwanath

et al. 2024

Molecular Oncology

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Metabolic dysfunction‐associated steatohepatitis‐driven hepatocellular carcinoma (MASH‐HCC) is a global clinical challenge for which there is a limited understanding of disease pathogenesis and a subsequent lack of therapeutic interventions. We previously identified that tumor necrosis factor‐alpha (TNF‐α) upregulated apoptosis antagonizing transcription factor (AATF) in MASH. Here, we investigated the effect of TNF‐α converting enzyme (TACE) inhibition as a promising targeted therapy against AATF‐mediated steatohepatitis to hepatocarcinogenesis. A preclinical murine model that recapitulates human MASH‐HCC was used in the study. C57Bl/6 mice were fed with chow diet normal water (CD) or western diet sugar water (WD) along with a low dose of carbon tetrachloride (CCl4; 0.2 μL·g−1, weekly) for 24 weeks. TACE activity, TNF‐α levels, and AATF expression were measured. The mice were treated with the TACE inhibitor Marimastat for 12 weeks, followed by analyses of liver injury, fibrosis, inflammation, and oncogenic signaling. In vitro experiments using stable clones of AATF control and AATF knockdown were also conducted. We found that AATF expression was upregulated in WD/CCl4 mice, which developed severe MASH at 12 weeks and advanced fibrosis with HCC at 24 weeks. WD/CCl4 mice showed increased TACE activity with reduced hepatic expression of sirtuin 1 (Sirt1) and tissue inhibitor of metalloproteinase 3 (Timp3). The involvement of the SIRT1/TIMP3/TACE axis was confirmed by the release of TNF‐α, which upregulated AATF, a key molecular driver of MASH‐HCC. Interestingly, TACE inhibition by Marimastat reduced liver injury, dyslipidemia, AATF expression, and oncogenic signaling, effectively preventing hepatocarcinogenesis. Furthermore, Marimastat inhibited the activation of JNK, ERK1/2, and AKT, which are key regulators of tumorigenesis in WD/CCl4 mice and in AATF control cells, but had no effect on AATF knockdown cells. This study shows that TACE inhibition prevents AATF‐mediated inflammation, fibrosis, and oncogenesis in MASH‐HCC, offering a potential target for therapeutic intervention.

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Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

Cited by 79 publications

References 176 publications

Epigenetic Biomarkers for the Diagnosis and Treatment of Liver Disease

Epigenetic Biomarkers for the Diagnosis and Treatment of Liver Disease

The Epigenetic Regulation of Microenvironment in Hepatocellular Carcinoma

TACE inhibition: a promising therapeutic intervention against AATF‐mediated steatohepatitis to hepatocarcinogenesis

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