Cancer epigenetics in clinical practice

Dávalos, Verónica; Esteller, Manel

doi:10.3322/caac.21765

Cited by 113 publications

(53 citation statements)

References 324 publications

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“…Extensive preclinical studies with drugs targeting the epigenetic proteins, including writers (DNA methyltransferase DNMTs, histone methyltransferase HMTs), readers (bromodomain and extraterminal BETs) and erasers (histone deacetylase HDACs), are being explored in pursuit of tumor inhibition. To date, FDA has approved seven agents -DNMT inhibitors (Azacitidine, Decitabine), EZH2 inhibitor (Tazemetostat), HDAC inhibitors (Vorinostat, Romidepsin, Belinostat, and Panobinostat) -for the treatment of diverse malignancies [20][21][22], several of which exhibited attractive antitumor effects in combination with CDK4/6 inhibitors [23][24][25]. For instance, FK228, an epigenetic eraser inhibitor (histone deacetylase inhibitor; HDACi) exhibiting anti-tumor effects against several types of solid tumors, has been shown to restrict cell proliferation and induce apoptosis in GC cells and suppress tumor growth in GC mouse models [26].…”

Section: Introductionmentioning

confidence: 99%

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

Feng

Zhou

et al. 2023

J Exp Clin Cancer Res

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Background Advanced gastric cancer (GC) is a lethal malignancy, harboring recurrent alterations in cell cycle pathway, especially the CDKN2A-CDK4/CDK6/CCND1 axis. However, monotherapy of CDK4/6 inhibitors has shown limited antitumor effects for GC, and combination treatments were urgently needed for CDK4/6 inhibitors. Methods Here, we performed a comprehensive analysis, including drug screening, pan-cancer genomic dependency analysis, and epigenetic sequencing to identify the candidate combination with CDK4/6 inhibitors. Mechanisms were investigated by bulk RNA-sequencing and experimental validation was conducted on diverse in vitro or in vivo preclinical GC models. Results We found that the BRD4 inhibitor JQ1 augments the antitumor efficacy of the CDK4/6 inhibitor abemaciclib (ABE). Diverse in vitro and in vivo preclinical GC models are examined and synergistic benefits from the combination therapy are obtained consistently. Mechanistically, the combination of ABE and JQ1 enhances the cell cycle arrest of GC cells and induces unique characteristics of cellular senescence through the induction of DNA damage, which is revealed by transcriptomic profiling and further validated by substantial in vitro and in vivo GC models. Conclusion This study thus proposes a candidate combination therapy of ABE and JQ1 to improve the therapeutic efficacy and worth further investigation in clinical trials for GC.

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Section: Introductionmentioning

confidence: 99%

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

Feng

Zhou

et al. 2023

J Exp Clin Cancer Res

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“…Promoter methylation regulates gene expression in different cancers ( 29 , 30 ). Methylation analysis showed that promoter methylation negatively correlated with GSDMB expression level in KIRC (p < 0.001), uterine corpus endometrial carcinoma (UCEC) (p < 0.01), lung adenocarcinoma (LUAD) (p < 0.001), and pancreatic adenocarcinoma (PAAD) (p < 0.001) ( Figures 2A–D ).…”

Section: Resultsmentioning

confidence: 99%

Systematic pan-cancer analysis identifies gasdermin B as an immunological and prognostic biomarker for kidney renal clear cell carcinoma

Liu

Xie

Ding³

et al. 2023

Front. Oncol.

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Gasdermin (GSDM)-mediated cell lytic death plays an essential role in immunity and tumorigenesis. Despite the association of gasdermin B (GSDMB) with the tumorigenesis of various cancers, whether GSDMB functions as a prognostic biomarker in renal cell carcinoma remains poorly understood. Here, we explored the potential immunological functions and the prognostic value of GSDMB across multiple tumors with The Cancer Genome Atlas (TCGA) and Genotype-Tissue Expression (GTEx) databases, including analyzing the relationship between GSDMB expression and prognosis, tumor–immune system interactions, immunomodulators, and immune cell infiltration of different tumors. Importantly, elevated expression of GSDMB is an essential factor for the poor prognosis of kidney renal clear cell carcinoma (KIRC) patients, suggesting that it might be helpful to predict a survival benefit from a clinical therapy regimen. Furthermore, GSDMB expression promoted the level of CD4+ T-cell infiltration of the tumors but is significantly negatively associated with immature dendritic cells (iDCs) in KIRC. Additionally, we identified TNFRSF25 and TNFSF14 as immunostimulators highly correlated with GSDMB expression. Kyoto Encyclopedia of Genes and Genomes (KEGG) and Gene Ontology (GO) enrichment analyses showed that GSDMB and its interacting proteins might affect tumor growth through the serine metabolism pathway. Our current results demonstrate a promising therapeutic strategy targeting GSDMB and provide new insights into GSDMB as an immunological and prognostic biomarker for KIRC.

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“…Furthermore, a study at the human genetic level found that ulcer-healing genes such as TFF2, PPARG, and RUNX3 can effectively recover from mucosal damage by coordinating methylation [38]. Folate is an essential substrate for the synthesis and maintenance of DNA methylation [39,40], which further strengthens the link between FA folate supplementation and GU.…”

Section: Discussionmentioning

confidence: 99%

Causal Association of Folic Acid Supplementary Therapy and Gastric Ulcer: A Mendelian Randomization Study

Huang

et al. 2023

Preprint

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Background. The incidence of gastric ulcer (GU) remains high worldwide with limited prevention. While promising animal experiments have suggested a potential preventive role of folic acid (FA) in the development of gastric ulcers, the lack of robust clinical evidence has hindered its widespread implementation as a preventative measure. Therefore, this research aims to determine the relationship between FA supplementation and GU genetically by Mendelian randomization (MR) approach, in order to establish a foundation for developing more effective preventative strategies for this condition. Methods. Genome-wide association studies (GWAS) investigating the association between folic acid or folate supplementation and gastric ulcers were sourced from the UK Biobank. The primary methods for Mendelian randomization analysis were the inverse variance-weighted (IVW) methods, including fixed-effect and random-effect IVW models. Other methods used to test the robustness of the results included simple model and median, weighted model and median, as well as penalized weighted median. Results. MR analysis was performed to investigate the causal effect of FA adjuvant therapy on GU. Seven single nucleotide polymorphisms (SNPs) of genetic loci associated with FA adjuvant therapy were identified. The random-effect and fixed-effect IVW models revealed that genetically predicted FA complementary therapy was significantly related to the reduction of GU risk (OR, 0.870; 95% CI, 0.826–0.917, p < 0.001; OR, 0.870; 95% CI, 0.825–0.918, p < 0.001). Similar results were also observed using simple mode (OR, 0.826; 95% CI, 0.724–0.943, p = 0.030), Weighted mode (OR, 0.828; 95% CI, 0.728–0.941, p = 0.028), simple median method (OR, 0.835; 95% CI, 0.773–0.901, p < 0.001), weighted median (OR, 0.854; 95% CI, 0.794–0.919, p < 0.001) and penalised weighted median (OR, 0.849; 95% CI, 0.789–0.914, p < 0.001). The association between FA supplementary therapy and GU was not considerably driven by any individual SNP according to the leave-one-out sensitivity analysis. Conclusions. This MR study provides evidence from a genetic perspective that FA supplementation may decrease the risk of gastric ulcer. Clinicians should prioritize the role of FA in preventing gastric ulcers among patients.

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Cancer epigenetics in clinical practice

Cited by 113 publications

References 324 publications

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

The BRD4 inhibitor JQ1 augments the antitumor efficacy of abemaciclib in preclinical models of gastric carcinoma

Systematic pan-cancer analysis identifies gasdermin B as an immunological and prognostic biomarker for kidney renal clear cell carcinoma

Causal Association of Folic Acid Supplementary Therapy and Gastric Ulcer: A Mendelian Randomization Study

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