Triterpenoid ursolic acid regulates the environmental carcinogen benzo[a]pyrene-driven epigenetic and metabolic alterations in SKH-1 hairless mice for skin cancer interception.

Polycyclic aromatic hydrocarbons (PAHs) are ubiquitous environmental carcinogens accountable to developing skin cancers. Recently, we reported that exposure to benzo[a]pyrene (B[a]P), a common PAH, causes epigenetic and metabolic alterations in the initiation, promotion and progression of non-melanoma skin cancer (NMSC). As a follow-up investigation, this study examines how dietary triterpenoid ursolic acid (UA) regulates B[a]P-driven epigenetic and metabolic pathways in SKH-1 hairless mice. Our results show UA intercepts against B[a]P-induced tumorigenesis at different stages of NMSC. Epigenomic cytosines followed by guanine residues (CpG) methyl-seq data showed UA diminished B[a]P-mediated differentially methylated regions (DMRs) profiles. Transcriptomic RNA-seq revealed UA revoked B[a]P-induced differentially expressed genes (DEGs) of skin cancer-related genes, such as leucine-rich repeat LGI family member 2 (Lgi2) and kallikrein-related peptidase 13 (Klk13), indicating UA plays a vital role in B[a]P-mediated gene regulation and its potential consequences in NMSC interception. Association analysis of DEGs and DMRs found that the mRNA expression of KLK13 gene was correlated with the promoter CpG methylation status in the early-stage comparison group, indicating UA could regulate the KLK13 by modulating its promoter methylation at an early stage of NMSC. The metabolomic study showed UA alters B[a]P-regulated cancer-associated metabolisms like thiamin metabolism, ascorbate and aldarate metabolism during the initiation phase; pyruvate, citrate and thiamin metabolism during the promotion phase; and beta-alanine and pathothenate coenzyme A (CoA) biosynthesis during the late progression phase. Taken together, UA reverses B[a]P-driven epigenetic, transcriptomic and metabolic reprogramming, potentially contributing to the overall cancer interception against B[a]P-mediated NMSC.

An Update on Potential Molecular Biomarkers of Dietary Phytochemicals Targeting Lung Cancer Interception and Prevention.

Since ancient times, dietary phytochemicals are known for their medicinal properties. They are broadly classified into polyphenols, terpenoids, alkaloids, phytosterols, and organosulfur compounds. Currently, there is considerable interest in their potential health effects against various diseases, including lung cancer. Lung cancer is the leading cause of cancer deaths with an average of five-year survival rate of lung cancer patients limited to just 14%. Identifying potential early molecular biomarkers of pre-malignant lung cancer cells may provide a strong basis to develop early cancer detection and interception methods. In this review, we will discuss molecular changes, including genetic alterations, inflammation, signal transduction pathways, redox imbalance, epigenetic and proteomic signatures associated with initiation and progression of lung carcinoma. We will also highlight molecular targets of phytochemicals during lung cancer development. These targets mainly consist of cellular signaling pathways, epigenetic regulators and metabolic reprogramming. With growing interest in natural products research, translation of these compounds into new cancer prevention approaches to medical care will be urgently needed. In this context, we will also discuss the overall pharmacokinetic challenges of phytochemicals in translating to humans. Lastly, we will discuss clinical trials of phytochemicals in lung cancer patients.

Metabolic rewiring and epigenetic reprogramming in leptin receptor-deficient db/db diabetic nephropathy mice.

BACKGROUND: Diabetic nephropathy (DN) is the leading cause of end-stage renal disease in the United States. Emerging evidence suggests that mitochondrial metabolism and epigenetics play an important role in the development and progression of DN and its complications. For the first time, we investigated the regulation of cellular metabolism, DNA methylation, and transcriptome status by high glucose (HG) in the kidney of leptin receptor-deficient db/db mice using multi-omics approaches. METHODS: The metabolomics was performed by liquid-chromatography-mass spectrometry (LC-MS), while epigenomic CpG methylation coupled with transcriptomic gene expression was analyzed by next-generation sequencing. RESULTS: LC-MS analysis of glomerular and cortex tissue samples of db/db mice showed that HG regulated several cellular metabolites and metabolism-related signaling pathways, including S-adenosylmethionine, S-adenosylhomocysteine, methionine, glutamine, and glutamate. Gene expression study by RNA-seq analysis suggests transforming growth factor beta 1 (TGFß1) and pro-inflammatory pathways play important roles in early DN. Epigenomic CpG methyl-seq showed HG revoked a list of differentially methylated regions in the promoter region of the genes. Integrated analysis of DNA methylation in the promoter regions of genes and gene expression changes across time points identified several genes persistently altered in DNA methylation and gene expression. Cyp2d22, Slc1a4, and Ddah1 are some identified genes that could reflect dysregulated genes involved in renal function and DN. CONCLUSION: Our results suggest that leptin receptor deficiency leading to HG regulates metabolic rewiring, including SAM potentially driving DNA methylation and transcriptomic signaling that could be involved in the progression of DN.

Butyrate Drives Metabolic Rewiring and Epigenetic Reprogramming in Human Colon Cancer Cells.

SCOPE: Butyrate (B) is a short-chain fatty acid produced by dietary fiber, known to inhibit histone deacetylases (HDACs) and possess cancer-preventive/anticancer effects. However, the role of B in metabolic rewiring, epigenomic reprogramming, transcriptomic network, NRF2 signaling, and eliciting cancer-preventive effects in colorectal cancer (CRC) HCT116 cell remains unclear. METHODS AND RESULTS: Sodium butyrate (NaB) dose-dependently inhibits the growth of CRC HCT116 cells. NaB inhibits NRF2/NRF2-target genes and blocks NRF2-ARE signaling. NaB increases NRF2 negative regulator KEAP1 expression through inhibiting its promoter methylation. Associative analysis of DEGs (differentially expressed genes) from RNA-seq and DMRs (differentially methylated regions) from CpG methyl-seq identified the tumor suppressor gene ABCA1 and tumor promote gene EGR3 are correlated with their promoters' CpG methylation indicating NaB regulates cancer markers through modulating their promoter methylation. NaB activated the mitochondrial tricarboxylic acid (TCA) cycle while inhibited the methionine metabolism which are both tightly coupled to the epigenetic machinery. NaB regulates the epigenetic enzymes/genes including DNMT1, HAT1, KDM1A, KDM1B, and TET1. Altogether, B's regulation of metabolites coupled to the epigenetic enzymes illustrates the potential underlying biological connectivity between metabolomics and epigenomics. CONCLUSION: B regulates KEAP1/NRF2 signaling, drives metabolic rewiring, CpG methylomic, and transcriptomic reprogramming contributing to the overall cancer-prevention/anticancer effect in the CRC cell model.

Epigenetics/epigenomics of triterpenoids in cancer prevention and in health.

Triterpenoids are a powerful group of phytochemicals derived from plant foods and herbs. Many reports have shown that they possess chemopreventive and chemotherapeutic effects not only in cell lines and animal models but also in clinical trials. Because epigenetic changes could potentially occur in the early stages of carcinogenesis preceding genetic mutations, epigenetics are considered promising targets in early interventions against cancer using epigenetic bioactive substances. The biological properties of triterpenoids in cancer prevention and in health have multiple mechanisms, including antioxidant and anti-inflammatory activities, cell cycle regulation, as well as epigenetic/epigenomic regulation. In this review, we will discuss and summarize the latest advances in the study of the pharmacological effects of triterpenoids in cancer chemoprevention and in health, including the epigenetic machinery.