Nutritional habits impinge on the health of the gastrointestinal (GI) tract, contributing to GI disorder progression. GI cancer is a widespread and aggressive tumor sensitive to nutritional changes. Indeed, specific nutritional expedients can be adopted to prevent GI cancer onset and to slow down disease activity. Moreover, the patient’s nutritional status impacts prognosis, quality of life, and chemotherapy tolerance. These patients encounter the highest frequency of malnourishment risk, a condition that can progressively evolve into cachexia. Clinical studies dealing with this topic stressed the importance of nutritional counseling and put under the spotlight nutrient delivery, the type of nutrient supplementation, and timing for the start of nutritional management. A medical practitioner well-prepared on the topic of nutrition and cancer should operate in the clinical team dedicated to these oncological patients. This specific expertise needs to be implemented as soon as possible to adopt nutritional interventions and establish a proper patient-tailored dietary regimen. The nutritional gap closure should be prompt during anticancer treatment to stabilize weight loss, improve treatment tolerability, and ameliorate survival rate. Recently, novel nutritional approaches were investigated to target the bidirectional link between epigenetics and metabolism, whose alteration supports the onset, progression, and therapeutic response of GI cancer patients.

The lncRNA metastasis-associated lung adenocarcinoma transcript 1 (MALAT1) promotes growth and progression in prostate cancer (PCa); however, little is known about its possible impact in PCa metabolism. The aim of this work has been the assessment of the metabolic reprogramming associated with MALAT1 silencing in human PCa cells and in an ex vivo model of organotypic slice cultures (OSCs). Cultured cells and OSCs derived from primary tumors were transfected with MALAT1 specific gapmers. Cell growth and survival, gene profiling, and evaluation of targeted metabolites and metabolic enzymes were assessed. Computational analysis was made considering expression changes occurring in metabolic markers following MALAT1 targeting in cultured OSCs. MALAT1 silencing reduced expression of some metabolic enzymes, including malic enzyme 3, pyruvate dehydrogenase kinases 1 and 3, and choline kinase A. Consequently, PCa metabolism switched toward a glycolytic phenotype characterized by increased lactate production paralleled by growth arrest and cell death. Conversely, the function of mitochondrial succinate dehydrogenase and the expression of oxidative phosphorylation enzymes were markedly reduced. A similar effect was observed in OSCs. Based on this, a predictive algorithm was developed aimed to predict tumor recurrence in a subset of patients. MALAT1 targeting by gapmer delivery restored normal metabolic energy pathway in PCa cells and OSCs.

The concept of the Myc (c-myc, n-myc, l-myc) oncogene as a canonical, DNA-bound transcription factor has consistently changed over the past few years. Indeed, Myc controls gene expression programs at multiple levels: directly binding chromatin and recruiting transcriptional coregulators; modulating the activity of RNA polymerases (RNAPs); and drawing chromatin topology. Therefore, it is evident that Myc deregulation in cancer is a dramatic event. Glioblastoma multiforme (GBM) is the most lethal, still incurable, brain cancer in adults, and it is characterized in most cases by Myc deregulation. Metabolic rewiring typically occurs in cancer cells, and GBM undergoes profound metabolic changes to supply increased energy demand. In nontransformed cells, Myc tightly controls metabolic pathways to maintain cellular homeostasis. Consistently, in Myc-overexpressing cancer cells, including GBM cells, these highly controlled metabolic routes are affected by enhanced Myc activity and show substantial alterations. On the other hand, deregulated cancer metabolism impacts Myc expression and function, placing Myc at the intersection between metabolic pathway activation and gene expression. In this review paper, we summarize the available information on GBM metabolism with a specific focus on the control of the Myc oncogene that, in turn, rules the activation of metabolic signals, ensuring GBM growth.

Background. Choline kinase alpha (CHKA), an essential gene in phospholipid metabolism, is among the modulated MALAT1-targeted transcripts in advanced and metastatic prostate cancer (PCa). Methods. We analyzed CHKA mRNA by qPCR upon MALAT1 targeting in PCa cells, which is characterized by high dose-responsiveness to the androgen receptor (AR) and its variants. Metabolome analysis of MALAT1-depleted cells was performed by quantitative High-resolution 1 H-Nuclear Magnetic Resonance (NMR) spectroscopy. In addition, CHKA genomic regions were evaluated by chromatin immunoprecipitation (ChIP) in order to assess MALAT1-dependent histone-tail modifications and AR recruitment. Results. In MALAT1-depleted cells, the decrease of CHKA gene expression was associated with reduced total choline-containing metabolites compared to controls, particularly phosphocholine (PCho). Upon MALAT1 targeting a significant increase in repressive histone modifications was observed at the CHKA intron-2, encompassing relevant AR binding sites. Combining of MALAT1 targeting with androgen treatment prevented MALAT1-dependent CHKA silencing in androgen-responsive (LNCaP) cells, while it did not in hormone-refractory cells (22RV1 cells). Moreover, AR nuclear translocation and its activation were detected by confocal microscopy analysis and ChIP upon MALAT1 targeting or androgen treatment. Conclusions. These findings support the role of MALAT1 as a CHKA activator through putative association with the liganded or unliganded AR, unveiling its targeting as a therapeutic option from a metabolic rewiring perspective.

Pancreatic ductal adenocarcinoma (PDAC) is a highly lethal cancer, with chronic metabolic disorders increasing risk and severity. Prolonged exposure to altered metabolism changes specific metabolite levels, impacting epigenetic landscape contributing neoplastic lesion acquisition. This study examines the interplay between metabolism and epigenetics in dysmetabolic-driven PDAC tumorigenesis, exploiting LSL-KrasG12D;PDX-1-Cre mice (KC mice) exposed to high-fat diet (HFD) and KRAS-mutated human pancreatic ductal epithelial (HPDE) cells. Untargeted metabolomics of HFD-fed KC pancreata reveals altered free fatty acid and elevated S-adenosyl methionine levels during tumorigenesis. Targeted metabolomics shows increased succinate alongside reduced α-ketoglutarate levels. This imbalance suggests an epigenetic derangement, targeting DNA methylation. In KRAS-mutated HPDE cells exposed to altered metabolism, the DNA demethylation complex of ten-to-eleven-translocation methylcytosine 1 and thymine DNA glycosylase (TDG) is disrupted, leading to iterative cytosine modification and apurinic/apyrimidinic (AP) site accumulation. Succinate directly binds TDG at arginine 275, hyperactivating it and increasing AP site formation. This alteration combined with the methylation-prone metabolic environment, impairs the base excision repair pathway by hypermethylating and downmodulating DNA ligases LIG1 and LIG3. This predisposes to genomic instability and pancreatic preneoplastic lesion development. These findings uncover a metabolic-epigenetic axis in dysmetabolic PDAC, highlighting how metabolite-driven epigenetic changes compromise DNA repair and drive tumorigenesis.