DNMT1-mediated methylation of BEX1 regulates stemness and tumorigenicity in liver cancer

Wang, Qian; Liang, Ning; Yang, Tao; Li, Yuedan; Li, Jing; Huang, Qian; Wu, Chen; Sun, Ligang; Zhou, Xingping; Cheng, Xiaobin; Zhao, Long; Wang, Gang; Chen, Zhangqian; He, Xianli; Liu, Chaoxu

doi:10.1016/j.jhep.2021.06.025

Cited by 83 publications

(61 citation statements)

References 28 publications

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“…Liver cancer, the sixth most common cancer, is the second leading cause of cancer mortality worldwide due to limited therapeutic interventions [136]. Liver cancer includes hepatoblastoma (HB) and HCC; the former is a common type of liver cancer reported in infants under 3 years of age, and the latter is the most common type of liver cancer documented, affecting 85-90% of liver cancer patients [118,[137][138][139]. SALL4 is reactivated in HCC, where 30-50% of tumors show high SALL4 expression [140].…”

Section: Hepatocellular Carcinomamentioning

confidence: 99%

SALL4 Oncogenic Function in Cancers: Mechanisms and Therapeutic Relevance

Sun

et al. 2022

IJMS

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SALL4, a member of the SALL family, is an embryonic stem cell regulator involved in self-renewal and pluripotency. Recently, SALL4 overexpression was found in malignant cancers, including lung cancer, hepatocellular carcinoma, breast cancer, gastric cancer, colorectal cancer, osteosarcoma, acute myeloid leukemia, ovarian cancer, and glioma. This review updates recent advances of our knowledge of the biology of SALL4 with a focus on its mechanisms and regulatory functions in tumors and human hematopoiesis. SALL4 overexpression promotes proliferation, development, invasion, and migration in cancers through activation of the Wnt/β-catenin, PI3K/AKT, and Notch signaling pathways; expression of mitochondrial oxidative phosphorylation genes; and inhibition of the expression of the Bcl-2 family, caspase-related proteins, and death receptors. Additionally, SALL4 regulates tumor progression correlated with the immune microenvironment involved in the TNF family and gene expression through epigenetic mechanisms, consequently affecting hematopoiesis. Therefore, SALL4 plays a critical oncogenic role in gene transcription and tumor growth. However, there are still some scientific hypotheses to be tested regarding whether SALL4 is a therapeutic target, such as different tumor microenvironments and drug resistance. Thus, an in-depth understanding and study of the functions and mechanisms of SALL4 in cancer may help develop novel strategies for cancer therapy.

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Section: Hepatocellular Carcinomamentioning

confidence: 99%

SALL4 Oncogenic Function in Cancers: Mechanisms and Therapeutic Relevance

Sun

et al. 2022

IJMS

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“…In the second type, DNMT3A and DNMT3B, together with their coactivator DNMT3L catalyze to new methyl groups to unmethylated cytosines [26]. DNMT1-mediated methylation of BEX1 regulates stemness and tumorigenicity in liver cancer [27]. However, the mechanism of DNMT3b/5mC activation and whether the DNMT3b/5mC axis is involved in the regulation of HCC remain unresolved.…”

Section: Discussionmentioning

confidence: 99%

CircASPH promotes hepatocellular carcinoma progression through methylation and expression of HAO2

Han

Xia

Tang

et al. 2022

Preprint

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Background CircRNAs have been reported to be related to hepatocellular carcinoma (HCC) development. Limited studies have revealed the expression profile of circRNAs in tumor and paratumour normal samples in HCC patients. Methods The expression of circRNAs, mRNA and miRNA was detected by Real-time PCR. An immunofluorescence assay was performed to detect the level of 5mC and 5hmC. Dual luciferase assay was used to confirm the interaction between miRNA and circRNA. CCK8, wound healing and transwell assays were used to check the viability, migration and invasion of HCC cells. Migration and invasion assays was used to confirm the metastasis in vivo. Results We found that circASPH was significantly increased in HCC tumor samples and that the level of circASPH was closely related to the overall survival (OS) of HCC patients. Mechanistically, circASPH could regulate the methylation of promoter and gene expression of Hydrocyanic Oxidase 2 (HAO2) to promote HCC progression by acting as a sponge for miR-370, which targeted the DNMT3b and increased the 5mC level. Conclusions Our study determined that circASPH could promote the methylation and expression of HAO2 and could be considered an important epigenetic regulator in HCC progression.

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“…It was recently shown that the DNA methyltransferase DNMT3L, might be responsible for the methylation of TNFRSF12A, which is overexpressed and methylated in alcohol-related HCC patients [61]. Moreover, a recent study showed that DNMT1 regulates the expression of BEX1, a gene necessary for the maintenance of tumor stemness and resistance to chemotherapy in HCC [62] (Figure 2). On the other hand, the glycine-N-methyltransferase (GNMT) was reported to be downregulated in HCC and its genetic deficiency was shown to trigger DNA hypermethylation, liver fibrosis, and cancer in mice [63].…”

Section: Dna Methylationmentioning

confidence: 99%

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer

Fan

Kam

Ramadori

2021

Cancers

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Metabolic reprogramming and epigenetic changes have been characterized as hallmarks of liver cancer. Independently of etiology, oncogenic pathways as well as the availability of different energetic substrates critically influence cellular metabolism, and the resulting perturbations often cause aberrant epigenetic alterations, not only in cancer cells but also in the hepatic tumor microenvironment. Metabolic intermediates serve as crucial substrates for various epigenetic modulations, from post-translational modification of histones to DNA methylation. In turn, epigenetic changes can alter the expression of metabolic genes supporting on the one hand, the increased energetic demand of cancer cells and, on the other hand, influence the activity of tumor-associated immune cell populations. In this review, we will illustrate the most recent findings about metabolic reprogramming in liver cancer. We will focus on the metabolic changes characterizing the tumor microenvironment and on how these alterations impact on epigenetic mechanisms involved in the malignant progression. Furthermore, we will report our current knowledge about the influence of cancer-specific metabolites on epigenetic reprogramming of immune cells and we will highlight how this favors a tumor-permissive immune environment. Finally, we will review the current strategies to target metabolic and epigenetic pathways and their therapeutic potential in liver cancer, alone or in combinatorial approaches.

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DNMT1-mediated methylation of BEX1 regulates stemness and tumorigenicity in liver cancer

Cited by 83 publications

References 28 publications

SALL4 Oncogenic Function in Cancers: Mechanisms and Therapeutic Relevance

SALL4 Oncogenic Function in Cancers: Mechanisms and Therapeutic Relevance

CircASPH promotes hepatocellular carcinoma progression through methylation and expression of HAO2

Metabolism-Associated Epigenetic and Immunoepigenetic Reprogramming in Liver Cancer

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