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Epigenetics encompasses reversible and heritable genomic changes in histones, DNA expression, and non-coding RNAs that occur without modifying the nucleotide DNA sequence. These changes play a critical role in modulating cell function in both healthy and pathological conditions. Dysregulated epigenetic mechanisms are implicated in various diseases, including cardiovascular disorders, neurodegenerative diseases, obesity, and mainly cancer. Therefore, to develop innovative therapeutic strategies, research for compounds able to modulate the complex epigenetic landscape of cancer is rapidly surging. Dietary phytochemicals, mostly flavonoids but also tetraterpenoids, organosulfur compounds, and isothiocyanates, represent biologically active molecules found in vegetables, fruits, medicinal plants, and beverages. These natural organic compounds exhibit epigenetic modulatory properties by influencing the activity of epigenetics key enzymes, such as DNA methyltransferases, histone acetyltransferases and deacetylases, and histone methyltransferases and demethylases. Due to the reversibility of the modifications that they induce, their minimal adverse effects, and their potent epigenetic regulatory activity, dietary phytochemicals hold significant promise as antitumor agents and warrant further investigation. This review aims to consolidate current data on the diverse epigenetic effects of the six major flavonoid subclasses, as well as other natural compounds, in the context of cancer. The goal is to identify new therapeutic epigenetic targets for drug development, whether as stand-alone treatments or in combination with conventional antitumor approaches. [ABSTRACT FROM AUTHOR]

Glyoxalase 2 (Glo2) is an enzyme of the glyoxalase system whose pathway parallels glycolysis and which aims to remove methylglyoxal (MGO). This study analyzed the possible additional roles of the Glo2 enzyme in breast cancer (MCF7) and non-cancer (HDF) cell lines, investigating its presence at the nuclear level and its potential involvement in cell proliferation and chemotherapy resistance. The results revealed that Glo2 is overexpressed in cancer cells, and its expression is higher during the proliferative (S and G2/M) phases of the cell cycle. The study also examined a post-translational modification (PTM) in which Glo2 could be involved, with S-glutathionylation revealing that Glo2 enhances this PTM in cancer cells both in the cytoplasm and nucleus. Inhibition of Glo2 by p-NCBG resulted in increased sensitivity to doxorubicin, a common chemotherapeutic agent. This suggests that Glo2 increases cancer cell resistance to chemotherapy, potentially through its role in regulating oxidative stress. These results highlight Glo2 as a potential therapeutic target to improve the efficacy of existing treatments. [ABSTRACT FROM AUTHOR]

This study assesses the expression of all TNF-related apoptosis-inducing ligand (TRAIL) receptors in pancreatic ductal adenocarcinoma (PDAC) tumor tissue. We aimed to include TRAIL receptor expression as an inclusion parameter in a future clinical study using a TRAIL-based therapy approach for PDAC patients. Considering the emerging influence of PDAC desmoplastic stroma on the efficacy of anti-PDAC therapies, this analysis was extended to tumor stromal cells. Additionally, we performed PDAC stroma characterization. Our retrospective cohort study (N=50) included patients with histologically confirmed PDAC who underwent surgery. The expression of TRAIL receptors (DR4, DR5, DcR1, DcR2, and OPG) in tumor and stromal cells was evaluated by immunohistochemistry (IHC). The amount of tumor stroma was assessed by anti-vimentin IHC and Mallory's trichrome staining. The prognostic impact was determined by the univariate Cox proportional hazards regression model. An extensive expression of functional receptors DR4 and DR5 and a variable expression of decoy receptors were detected in PDAC tumor and stromal cells. Functional receptors were detected also in metastatic tumor and stromal cells. A poor prognosis was associated with low or absent expression of decoy receptors in tumor cells of primary PDAC. After assessing that almost 80% of tumor mass was composed of stroma, we correlated a cellular-dense stroma in primary PDAC with reduced relapse-free survival. We demonstrated that TRAIL functional receptors are widely expressed in PDAC, representing a promising target for TRAIL-based therapies. Further, we demonstrated that a low expression of DcR1 and the absence of OPG in tumor cells, as well as a cellular-dense tumor stroma, could negatively impact the prognosis of PDAC patients., Competing Interests: MD and GGr hold patents in the field of cell and gene therapy and declare a consultancy role, research funding, and stock ownership with Rigenerand Srl. MCS declares stock ownership with Rigenerand Srl. MDa and MCS are employees of Rigenerand Srl. The other authors do not declare any competing interests., (AJCR Copyright © 2021.)