Mechanistic roles of mutant p53 governing lipid metabolism

Metabolic reprogramming of cancer cells by various acquired mutations provides support for rapid proliferation and growth in the tumor microenvironment. Mutations in the TP53 gene are the most common mutation found across all human cancers. Commonly referred to as “the guardian of the genome”, p53 has a well-established role as a tumor suppressor by mediating checkpoint integrity and protecting cells from DNA damage. To date, the many functional roles of p53 extending beyond its classical function and exerting control over metabolic processes continues to confound the field. Recently, emerging roles for p53 in mediating lipid metabolism have come to light with intriguing metabolic roles in regulating cholesterol homeostasis and lipid droplet formation. Herein, we will seek to unify the mechanisms by which absence of functional p53, as well as stable mutant forms of p53, exert control over these lipid metabolism programs. Of equal importance, synthetic lethal phenotypes in the context of mutant p53 and aberrant lipid homeostasis offer new possible targets in the therapeutic landscape. This review aims to characterize the mechanisms by which p53 exerts control over these pathways and examine how precision medicine may benefit from tumor subtyping of p53 mutations.