Epigenetic Mechanisms in Gastric Cancer: Potential New Therapeutic Opportunities

Canale, Matteo; Casadei-Gardini, Andrea; Ulivi, Paola; Arechederra, María; Berasain, Carmen; Lollini, Pier‐Luigi; Fernández‐Barrena, Maite G.; Avila, Matı́as A.

doi:10.3390/ijms21155500

Cited by 38 publications

(33 citation statements)

References 156 publications

(185 reference statements)

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“…The epigenetic modifications in modulating expressions of many cancerrelated genes have played essential roles in GC initiation and progression and formed novel epigenetic signature (42)(43)(44). Targeting key epigenetic drivers would notably suppress cancer progression for GC (45). As is well known, PRC1 and PRC2 co-operate to regulate epigenetics via histone modification incorporating the methylation of histone H3K27 and monoubiquitination of histone H2AK119 (46,47).…”

Section: Discussionmentioning

confidence: 99%

Chromobox 4 (CBX4) promotes tumor progression and stemness via activating CDC20 in gastric cancer

Chen

Wang

et al. 2022

J Gastrointest Oncol

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Background: The Chromobox homolog 4 (CBX4) has been found to be overexpressed in multiple malignancies. However, the associations between CBX4 and gastric cancer (GC) have remained unclear. This study aimed to determine the biological roles of CBX4 in GC and identify effective therapeutic targets. Methods:The 3-(4,5-dimethylthiazol-2-yl) (MTT) assays were used to screen CBX family members.Differential analysis was utilized to evaluate the CBX4 levels. Kaplan-Meier analysis was used to perform prognostic analysis. Western blotting assay, quantitative polymerase chain reaction (qPCR) assay and immunohistochemistry (IHC) were used to assess CBX4 expressions. Colony formation assay, Cell Counting Kit-8 (CCK-8) assay, and Transwell assay were used to assess progression features of cells. The tail vein injection model was utilized to determine the metastatic efficacy of GC cells. Tumor sphere formation assay was used to assess tumor stemness maintenance ability. Chromatin immunoprecipitation (ChIP)-qPCR assay was used to evaluate the associations between CBX4 and CDC20. A subcutaneous tumor model was used to assess the in vivo growth ability of GC. Results:The MTT assay revealed that only CBX4 inhibition could lead to notable restriction of GC growth, as compared to others. Differential analysis suggested that CBX4 was upregulated in tumor samples relative to normal tissues. Less favorable overall survival (OS) outcomes were noticed in GC patients with high CBX4 in comparison to those with low CBX4. High CBX4 could notably enhance cell proliferation capacity, migration ability, and in vivo metastatic efficacy. Gene set enrichment analysis (GSEA) indicated the relationships between CBX4 and GC stemness, and CBX4 overexpression could remarkably elevate self-renewal ability of GC cells. In addition, CBX4 could mainly promote CDC20 messenger RNA (mRNA) levels, and targeting CBX4 suppressed the relative CDC20 levels. The ChIP-qPCR assay further demonstrated that CBX4 coordinated with H3K4me3 to bind at the CDC20 promoter region. Additionally, CBX4 depended on CDC20 to drive GC growth. Lastly, downregulated CBX4 could notably inhibit the growth of GC in vivo.Conclusions: This study highlights the oncogenic roles of CBX4 in GC. CBX4 activates CDC20 to maintain stemness features of GC, thereby creating therapeutic vulnerabilities in the treatment of GC.

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Section: Discussionmentioning

confidence: 99%

Chromobox 4 (CBX4) promotes tumor progression and stemness via activating CDC20 in gastric cancer

Chen

Wang

et al. 2022

J Gastrointest Oncol

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“…Therefore, understanding the pathological mechanisms, especially proliferation and metastasis, is critical to direct GC therapy. Although non-coding RNAs have important contributions to cell–cell communication, revealing the complex interactions between tumor cells, tumor microenvironment cells and immune cells, and analyzing their content in body fluids have become mainstream in biomarker identification [ 20 ], increasing evidence suggests that alterations in epigenetic mechanisms can guide cancer onset and progression, such as DNA methylation, histone methylation modifications and histone acetylation [ 21 ]. In recent years, researchers identified m6A RNA modifications as epigenetic regulators involved in the dynamic and reversible control of RNA structure and function in tumors, including colorectal, liver, breast, nasopharyngeal and gastric cancers [ 22 , 23 , 24 ].…”

Section: Discussionmentioning

confidence: 99%

The m6A Methyltransferase METTL3-Mediated N6-Methyladenosine Modification of DEK mRNA to Promote Gastric Cancer Cell Growth and Metastasis

Zhang

Wang

et al. 2022

IJMS

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Gastric cancer (GC) is the fifth most common cancer and the third deadliest cancer in the world, and the occurrence and development of GC are influenced by epigenetics. Methyltransferase-like 3 (METTL3) is a prominent RNA n6-adenosine methyltransferase (m6A) that plays an important role in tumor growth by controlling the work of RNA. This study aimed to reveal the biological function and molecular mechanism of METTL3 in GC. The expression level of METTL3 in GC tissues and cells was detected by qPCR, Western blot and immunohistochemistry, and the expression level and prognosis of METTL3 were predicted in public databases. CCK-8, colony formation, transwell and wound healing assays were used to study the effect of METTL3 on GC cell proliferation and migration. In addition, the enrichment effect of METTL3 on DEK mRNA was detected by the RIP experiment, the m6A modification effect of METTL3 on DEK was verified by the MeRIP experiment and the mRNA half-life of DEK when METTL3 was overexpressed was detected. The dot blot assay detects m6A modification at the mRNA level. The effect of METTL3 on cell migration ability in vivo was examined by tail vein injection of luciferase-labeled cells. The experimental results showed that METTL3 was highly expressed in GC tissues and cells, and the high expression of METTL3 was associated with a poor prognosis. In addition, the m6A modification level of mRNA was higher in GC tissues and GC cell lines. Overexpression of METTL3 in MGC80-3 cells and AGS promoted cell proliferation and migration, while the knockdown of METTL3 inhibited cell proliferation and migration. The results of in vitro rescue experiments showed that the knockdown of DEK reversed the promoting effects of METTL3 on cell proliferation and migration. In vivo experiments showed that the knockdown of DEK reversed the increase in lung metastases caused by the overexpression of METTL3 in mice. Mechanistically, the results of the RIP experiment showed that METTL3 could enrich DEK mRNA, and the results of the MePIP and RNA half-life experiments indicated that METTL3 binds to the 3’UTR of DEK, participates in the m6A modification of DEK and promotes the stability of DEK mRNA. Ultimately, we concluded that METTL3 promotes GC cell proliferation and migration by stabilizing DEK mRNA expression. Therefore, METTL3 is a potential biomarker for GC prognosis and a therapeutic target.

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“…Moreover, CDH1 hypermethylation could be a potential novel drug target for developing personalized therapies [ 34 , 35 ]. However, further studies on a larger number of patients with GC of different histotypes are necessary to confirm our results and to deeply understand the role of enhancer methylation in the regulation of CDH1 gene.…”

Section: Discussionmentioning

confidence: 99%

Genetic and Epigenetic Alterations of CDH1 Regulatory Regions in Hereditary and Sporadic Gastric Cancer

et al. 2021

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E-cadherin is a key player in gastric cancer (GC) and germline alterations of CDH1, its encoding gene, are responsible for Hereditary Diffuse Gastric Cancer (HDGC) syndrome. This study aimed at elucidating the role of genetic variants and DNA methylation of CDH1 promoter and enhancers in the regulation of gene expression. For this purpose, we analyzed genetic variants of the CDH1 gene through Next-Generation Sequencing (NGS) in a series of GC cell lines (NCI-N87, KATO-III, SNU-1, SNU-5, GK2, AKG, KKP) and the corresponding CDH1 expression levels. By bisulfite genomic sequencing, we analyzed the methylation status of CDH1 regulatory regions in 8 GC cell lines, in a series of 13 sporadic GC tissues and in a group of 20 HDGC CDH1-negative patients and 6 healthy controls. The NGS analysis on CDH1 coding and regulatory regions detected genetic alterations in 3 out of 5 GC cell lines lacking functional E-cadherin. CDH1 regulatory regions showed different methylation patterns in patients and controls, GC cell lines and GC tissues, expressing different E-cadherin levels. Our results showed that alterations in terms of genetic variants and DNA methylation patterns of both promoter and enhancers are associated with CDH1 expression levels and have a role in its regulation.

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Epigenetic Mechanisms in Gastric Cancer: Potential New Therapeutic Opportunities

Cited by 38 publications

References 156 publications

Chromobox 4 (CBX4) promotes tumor progression and stemness via activating CDC20 in gastric cancer

Chromobox 4 (CBX4) promotes tumor progression and stemness via activating CDC20 in gastric cancer

The m6A Methyltransferase METTL3-Mediated N6-Methyladenosine Modification of DEK mRNA to Promote Gastric Cancer Cell Growth and Metastasis

Genetic and Epigenetic Alterations of CDH1 Regulatory Regions in Hereditary and Sporadic Gastric Cancer

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