Non-coding RNAs, metabolic stress and adaptive mechanisms in cancer

Metabolic reprogramming in cancer describes the multifaceted alterations in metabolism that contribute to tumorigenesis. Major determinants of metabolic phenotypes are the changes in signalling pathways associated with oncogenic activation together with cues from the tumor microenvironment. Therein, depleted oxygen and nutrient levels elicit metabolic stress, requiring cancer cells to engage adaptive mechanisms. Non-coding RNAs (ncRNAs) act as regulatory elements within metabolic pathways and their widespread dysregulation in cancer contributes to altered metabolic phenotypes. Indeed, ncRNAs are the regulatory accomplices of many prominent effectors of metabolic reprogramming including c-MYC and HIFs that are activated by metabolic stress. By example, this review illustrates the range of ncRNAs mechanisms impacting these effectors throughout their DNA-RNA-protein lifecycle along with presenting the mechanistic roles of ncRNAs in adaptive responses to glucose, glutamine and lipid deprivation. We also discuss the facultative activation of metabolic enzymes by ncRNAs, a phenomenon which may reflect a broad but currently invisible level of metabolic regulation. Finally, the translational challenges associated with ncRNA discoveries are discussed, emphasizing the gaps in knowledge together with importance of understanding the molecular basis of ncRNA regulatory mechanisms.