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Converging on DKK1 to drive metastatic HCC
Hepatocellular carcinoma (HCC) is a common form of liver cancer. The Wnt signaling protein DKK1 and the growth factor receptor EGFR are abundant in HCC and are associated with metastatic progression and poor prognosis in patients. Niu et al. found that these molecular markers are linked. The activation of EGFR in HCC cells induced DKK1 expression through parallel pathways: MEK-ERK pathway–dependent nuclear translocation of the kinase PKM2 and PI3K-AKT pathway–dependent activation of the acetyltransferase p300. These pathways converged on modifying histone H3 at the DKK1 promoter to activate gene transcription. The findings reveal previously unidentified targets that could be therapeutically targeted in patients with HCC.
Abstract
The protein Dickkopf-1 (DKK1) is frequently overexpressed at the transcript level in hepatocellular carcinoma (HCC) and promotes metastatic progression through the induction of β-catenin, a Wnt signaling effector. We investigated how DKK1 expression is induced in HCC and found that activation of the epidermal growth factor receptor (EGFR) promoted parallel MEK-ERK and PI3K-Akt pathway signaling that converged to epigenetically stimulate DKK1 transcription. In HCC cell lines stimulated with EGF, EGFR-activated ERK phosphorylated the kinase PKM2 at Ser37, which promoted its nuclear translocation. Also in these cells, EGFR-activated Akt phosphorylated the acetyltransferase p300 at Ser1834. Subsequently, PKM2 and p300 mediated the phosphorylation and acetylation, respectively, of histone H3 at the DKK1 promoter, which synergistically enhanced DKK1 transcription. The mechanism was supported with mutational analyses in cells and in a chemically induced HCC model in rats. The findings suggest that dual inhibition of the MEK and PI3K pathways might suppress the expression of DKK1 and, consequently, tumor metastasis in patients with HCC.
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