Abstract
Hotspot p53 mutant proteins often gain novel functions in promoting tumor metastases. However, the molecular mechanisms by which mutant p53 exerts gain-of-function in cancer are not totally understood. In this study, we demonstrate that hotspot mutant p53, p53-R273H, promotes cell scattering growth and migration via inhibiting the expression of Krupple-like factor 6 (KLF6), a Zinc finger transcription factor and a documented tumor suppressor. Restoration of KLF6 increases the expression of E-cadherin downregulated by p53-R273H and inhibits p53-R273H-induced cell migration and tumor metastasis. Further, p53-R273H reduces KLF6 transcription by upregulating EGFR expression which in turn activates AKT–FOXO1 axis. Pharmacological inhibitor of AKT, MK2206, rescues KLF6 expression and suppresses p53-R273H-induced cell migration. Clinical analyses reveal that KLF6 expression is decreased in human breast cancer specimens harboring p53 mutations, and negatively correlated with EGFR expression in human breast cancer. In addition, low expression of KLF6 is associated with poor overall survival (OS) and relapse-free survival (RFS) in p53 mutated human breast cancer patients. Together, these results reveal an important role for EGFR–AKT–FOXO1–KLF6–E-cadherin axis in mutant p53-induced cell migration and tumor metastasis.
Highlights
Hotspot p53 mutant proteins often gain novel functions in promoting tumor metastases
We demonstrate that p53-R273H promotes tumor metastasis by downregulation of Krupple-like factor 6 (KLF6) gene transcription via the EGFR-AKT-FOXO1 pathway. p53
This study demonstrates that mutant p53 represses KLF6–E-cadherin axis via EGFR/AKT/ FOXO1 signal pathway to promote cancer cell migration and tumor metastasis (Fig. 5g)
Summary
P53-R273H promotes cell migration via downregulation of KLF6 and E-cadherin expression p53 is the most frequently mutated gene in human cancers. We hypothesized that p53-R273H downregulates E-cadherin expression via inhibition of KLF6 With this regard, we found that p53R273H, and other hotspot mutants, p53-R175H and p53-R248W, significantly inhibited KLF6 expression at both mRNA (Fig. 2a) and protein levels (Fig. 2b), and promoted cell migration (Fig. 2c). Ectopic expression of p53-R273H in p53-ablated MCF-10A cells dramatically inhibited KLF6 and Ecadherin expression (Fig. 2h) Together, these data indicate that p53 hotspot mutant proteins can suppress transcription of KLF6 and E-cadherin, concomitant with increased cell migration. Restoration of KLF6 expression effectively recovered expression of E-cadherin suppressed by p53-R273H and significantly inhibited cell migration induced by p53R273H in MCF-10A or HCC1806 cells (Fig. 3b, c). This study demonstrates that mutant p53 represses KLF6–E-cadherin axis via EGFR/AKT/ FOXO1 signal pathway to promote cancer cell migration and tumor metastasis (Fig. 5g)
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