p53-Mediated Indirect Regulation on Cellular Metabolism: From the Mechanism of Pathogenesis to the Development of Cancer Therapeutics

The transcription factor p53 is the most well-characterized tumor suppressor involved in multiple cellular processes, which has expanded to the regulation of metabolism in recent decades. Accumulating evidence reinforces the link between the disturbance of p53-relevant metabolic activities and tumor development. However, a full-fledged understanding of the metabolic roles of p53 and the underlying detailed molecular mechanisms in human normal and cancer cells remain elusive, and persistent endeavor is required to foster the entry of drugs targeting p53 into clinical use. This mini-review summarizes the indirect regulation of cellular metabolism by wild-type p53 as well as mutant p53, in which mechanisms are categorized into three major groups: through modulating downstream transcriptional targets, protein-protein interaction with other transcription factors, and affecting signaling pathways. Indirect mechanisms expand the p53 regulatory networks of cellular metabolism, making p53 a master regulator of metabolism and a key metabolic sensor. Moreover, we provide a brief overview of recent achievements and potential developments in the therapeutic strategies targeting mutant p53, emphasizing synthetic lethal methods targeting mutant p53 with metabolism. Then, we delineate synthetic lethality targeting mutant p53 with its indirect regulation on metabolism, which expands the synthetic lethal networks of mutant p53 and broadens the horizon of developing novel therapeutic strategies for p53 mutated cancers, providing more opportunities for cancer patients with mutant p53. Finally, the limitations and current research gaps in studies of metabolic networks controlled by p53 and challenges of research on p53-mediated indirect regulation on metabolism are further discussed.