Functional preservation of tumor suppressor protein p53 by formation of baicalein-induced higher-order multimers

p53 protein is an important transcription factor for suppressing oncogenesis. p53 is inactivated by the amorphous or amyloid aggregation, mainly via its aggregation-prone p53 DNA-binding domain (p53-DBD). Amyloid-like aggregation inhibition or MDM2-dependent degradation has been well studied, but amorphous aggregation inhibition, which is strongly associated with the loss of DNA-binding ability, has been poorly studied. We evaluated the p53 amorphous aggregation inhibitory activity of 16 flavonoids. As a result, baicalein, known as a flavonoid with anticancer activity, suppresses both the amorphous and amyloid aggregation of p53-DBD. Interestingly, baicalein promoted a higher-order multimer formation without structural transition. The cell-based assays showed an increase in nuclear p53 and activation of the p53 pathway following treatment with baicalein. We hypothesized that baicalein prevents either degradation or inactivation of p53 by promoting the multimer formation of nuclear p53, resulting in the preservation of p53 with transcriptional activity, which is necessary for anticancer activity.