Targeting Epigenetic Regulation for Cancer Therapy

A special issue of Pharmaceuticals (ISSN 1424-8247). This special issue belongs to the section "Pharmacology".

Deadline for manuscript submissions: 30 September 2026 | Viewed by 1537

Special Issue Editors


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Guest Editor
Institute of Basics of Health Sciences, Midwifery and Health Visiting, Faculty of Health Sciences, University of Pécs, Vörösmarty Mihály Str. 4, 7621 Pécs, Hungary
Interests: cancer; gene expression; phytochemicals; molecular genetics; epidemiology
Special Issues, Collections and Topics in MDPI journals

E-Mail Website
Guest Editor
Faculty of Health Sciences, University of Pécs, Vörösmarty Mihály Str. 4, 7621 Pécs, Hungary
Interests: gastrointestinal cancers; phytotherapeutics; microbial and molecular genetics; pyhtochemistry; epidemiology
Special Issues, Collections and Topics in MDPI journals

Special Issue Information

Dear Colleagues,

Epigenetics has emerged as a critical area of study in recent decades, revealing how heritable changes in gene expression occur without altering the DNA sequence. DNA methylation, initially the most studied epigenetic mechanism, has now been complemented by a broader understanding of histone modifications, chromatin remodeling, and non-coding RNAs.

This Special Issue aims to explore the complex network of epigenetic factors beyond DNA methyltransferases (DNMTs) that regulate gene activity, genome stability, and cellular identity. We welcome contributions from a broad range of biological systems and disciplines that address how different epigenetic mechanisms function, interact, and contribute to physiological or pathological processes, with a particular emphasis on their implications for cancer biology and therapy. Understanding how epigenetic alterations drive tumor progression, resistance, and immune evasion may offer promising avenues for developing more precise and effective cancer treatments.

Recent advances in epigenomic technologies, such as ChIP-seq, ATAC-seq, and single-cell epigenomics, are rapidly expanding our understanding of chromatin states and gene regulatory networks. This issue will feature research that uncovers novel epigenetic regulators, their mechanisms of action, and their potential as therapeutic targets—especially in cancer, where epigenetic interventions are increasingly being investigated as part of combination therapies or as standalone approaches. Studies elucidating the epigenetic basis of therapy resistance, tumor heterogeneity, or immune modulation are particularly welcome.

We invite original research articles, reviews, and perspective papers that investigate epigenetic mechanisms beyond DNMTs, including histone-modifying enzymes, chromatin remodelers, and non-coding RNAs. Both experimental and computational studies are encouraged, as well as work spanning molecular, cellular, organismal, or environmental levels. Submissions that explore translational aspects—such as epigenetic biomarkers or the development of epigenetic drugs for cancer therapy—are of particular interest. All topics related to the central theme of epigenetic regulation—including novel insights, emerging technologies, comparative analyses, and interdisciplinary approaches—are welcome.

Dr. Bence Raposa
Dr. John M. Macharia
Guest Editors

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Keywords

  • epigenetics
  • chromatin remodeling
  • histone modifications
  • non-coding RNAs
  • gene regulation
  • cancer therapy
  • epigenetic biomarkers
  • therapeutic targets

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Published Papers (2 papers)

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Research

14 pages, 2510 KB  
Article
Effects of the Hypomethylating Agent Guadecitabine on Peripheral Blood Mononuclear Cell Methylomes and Immune Cell Populations in Small-Cell Lung Cancer Patients
by Elnaz Abbasi Farid, Shu Zhang, Zhen Fu, Collin M. Coon, Daniela Matei, Shadia I. Jalal and Kenneth P. Nephew
Pharmaceuticals 2026, 19(4), 542; https://doi.org/10.3390/ph19040542 - 28 Mar 2026
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Abstract
Background/Objectives: Epigenetic modifications, particularly DNA methylation, contribute to tumor progression and therapy resistance. Guadecitabine, a hypomethylating agent (HMA), has shown promising clinical activity when combined with carboplatin in preclinical models. We evaluated the combination of guadecitabine with carboplatin as a second-line treatment for [...] Read more.
Background/Objectives: Epigenetic modifications, particularly DNA methylation, contribute to tumor progression and therapy resistance. Guadecitabine, a hypomethylating agent (HMA), has shown promising clinical activity when combined with carboplatin in preclinical models. We evaluated the combination of guadecitabine with carboplatin as a second-line treatment for extensive-stage small-cell lung cancer (SCLC; NCT03913455), one of the deadliest malignancies. Here, we report methylome changes in peripheral blood mononuclear cells (PBMCs) collected at baseline and during treatment from patients on the trial. Methods: PMBC DNA was analyzed using Infinium HumanMethylationEPIC v1.0 bead chips. Data were processed, and differentially methylated positions (DMPs) were identified and analyzed for pathway enrichment using bioinformatic approaches, and immune deconvolution analyses were conducted to investigate the impact on immune cell composition. Results: Direct comparison of PBMCs between cycle 2 day 5 (C2D5; post-treatment) vs. cycle 1 day 1 (C1D1; pre-treatment) revealed a greater number of hypomethylated DMPs (380 DMPs in C2D5 vs. C1D1 PBMCs; p < 0.05, |β| > 20%). Moreover, when first compared with normal PBMCs from cancer-free controls, the number of hypomethylated DMPs was even greater in C2D5 than in C1D1 (1771 vs. 237 DMPs, respectively; p < 0.05, |β| > 20%). Long interspersed nucleotide elements-1 (LINE-1) were significantly hypomethylated in PBMCs after HMA treatment (C2D5 vs. C1D1). Pathway analysis of hypomethylated DMPs revealed significant alterations in key signaling pathways, including NF-κB, Rho GTPase, and pulmonary fibrosis in C1D1 vs. C2D5. Normal PBMCs to C1D1 PBMCs revealed changes in IL-3 signaling, Fcγ receptor-mediated phagocytosis, and molecular mechanisms of cancer. Deconvolution analysis revealed a greater percentage of monocytes in C1D1 vs. normal PBMCs; after HMA treatment, percentages of monocytes and B cells decreased, while the eosinophil percentage increased in C1D1 vs. C2D5. Conclusions: HMA treatment has a global impact on PBMC methylomes in cancer patients. DNA methylation changes were associated with biological pathways related to PBMC function, and shifts in distinct immune cell populations were observed. Full article
(This article belongs to the Special Issue Targeting Epigenetic Regulation for Cancer Therapy)
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23 pages, 3923 KB  
Article
Curcumin in High Doses Reverses the UV-B-Induced DNMT and HDAC Upregulation In Vitro: A Novel Anti-Cancer Approach?
by Afshin Zand, Bence L. Raposa, Dávid Szép, John M. Macharia, Ghodratollah Nowrasteh, Ferenc Budán and Tímea Varjas
Pharmaceuticals 2026, 19(3), 496; https://doi.org/10.3390/ph19030496 - 17 Mar 2026
Viewed by 636
Abstract
Background/Objectives: The primary mechanisms driving UV-induced carcinogenesis include DNA damage leading to mutations, and reactive oxygen species (ROS) formation that can cause inflammation, immunosuppression, alteration of the structure of proteins, including transcription factors, and carcinogenesis through epigenetic modifications. Curcumin has the potential to [...] Read more.
Background/Objectives: The primary mechanisms driving UV-induced carcinogenesis include DNA damage leading to mutations, and reactive oxygen species (ROS) formation that can cause inflammation, immunosuppression, alteration of the structure of proteins, including transcription factors, and carcinogenesis through epigenetic modifications. Curcumin has the potential to inhibit DNA-methyltransferases (DNMTs) and histone deacetylases (HDACs), but this has not been examined yet at the gene-expression level. In this article, we aimed to explore the potential protective effect of curcumin against UV radiation-induced DNMT1, DNMT3A, DNMT3B, HDAC5, and HDAC6 expression in immortalized keratinocytes (HaCaT), hepatocellular carcinoma (HepG2), and lung adenocarcinoma (A549) cells. Methods: Cells were exposed to UV-B radiation for different periods and treated with curcumin at different concentrations to evaluate dose-related trends in DNMT and HDAC gene expression compared with untreated UV-exposed cells. Results: UV exposure increased the DNMT and HDAC gene expression levels in the examined cells dose-dependently. Curcumin exposure resulted in decreased mRNA expression levels of DNMT and HDAC gene expression. In our experimental setup curcumin modulated the transcription of DNMT and HDAC genes in A549 and HaCaT cells in a dose-dependent manner. In HepG2 cells, UV-B induced a less pronounced, but still significant, increase in the examined gene expression levels. This effect was also dose-dependently decreased by curcumin, although less markedly. Conclusions: Future studies are warranted to examine if curcumin combined with other chemopreventive agents through the HDAC and DNMT inhibitory activity at the gene expression level can exert a synergistic effect and may potentially supplement cancer therapeutic strategies. Full article
(This article belongs to the Special Issue Targeting Epigenetic Regulation for Cancer Therapy)
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