Mutant p53 Regulates Pyruvate Dehydrogenase Kinase 1 (PDK1) to Promote Proliferation and Migration in Breast Cancer.

Tumor suppressor p53 is the most frequently mutated gene in cancers. Mutations in p53 not only result in the loss of its classical tumor-suppressive functions but also confer new oncogenic properties. The protein stabilization of mutant p53 (mutp53) is a prerequisite for gain-of-function manifestation. Here, we report the novel mechanism that pyruvate dehydrogenase kinase1 (PDK1) modulates both wild-type and mutant p53, and facilitates proliferation and migration of TP53 mutant breast cancer. On the one hand, we identified PDK1 as a direct transcriptional repression target of wild-type p53, whereas transcriptional activation of PDK1 in mutp53 cells is initiated by the EGR1 axis. On the other hand, PDK1 promoted mutp53 protein accumulation by binding to mutp53 and inhibiting its degradation. Taken together, mutp53 activated a positive feedback loop by upregulating PDK1 to enhance p53 protein stability and promote the malignancy of breast cancer. Moreover, PDK1 inhibition increased the therapeutic effect of APR-246 on TP53 mutant breast cancer in xenograft tumors. Our results suggested that intervention of PDK1 could potentially emerge as a new therapeutic strategy to impede the progression of TP53 mutant breast cancer.