Metabolic Dysregulations and Epigenetics: A Bidirectional Interplay that Drives Tumor Progression

Cancer has been considered, for a long time, a genetic disease where mutations in key regulatory genes drive tumor initiation, growth, metastasis, and drug resistance. Instead, the advent of high-throughput technologies has revolutionized cancer research, allowing to investigate molecular alterations at multiple levels, including genome, epigenome, transcriptome, proteome, and metabolome and showing the multifaceted aspects of this disease. The multi-omics approaches revealed an intricate molecular landscape where different cellular functions are interconnected and cooperatively contribute to shaping the malignant phenotype. Recent evidence has brought to light how metabolism and epigenetics are highly intertwined, and their aberrant crosstalk can contribute to tumorigenesis. The oncogene-driven metabolic plasticity of tumor cells supports the energetic and anabolic demands of proliferative tumor programs and secondary can alter the epigenetic landscape via modulating the production and/or the activity of epigenetic metabolites. Conversely, epigenetic mechanisms can regulate the expression of metabolic genes, thereby altering the metabolome, eliciting adaptive responses to rapidly changing environmental conditions, and sustaining malignant cell survival and progression in hostile niches. Thus, cancer cells take advantage of the epigenetics-metabolism crosstalk to acquire aggressive traits, promote cell proliferation, metastasis, and pluripotency, and shape tumor microenvironment. Understanding this bidirectional relationship is crucial to identify potential novel molecular targets for the implementation of robust anti-cancer therapeutic strategies.