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.

蛋白质 Dickkopf-1 (DKK1) 在肝细胞癌 (HCC) 中经常在转录水平上过表达，并通过诱导 β-连环蛋白（一种 Wnt 信号传导效应器）促进转移进展。我们研究了如何在 HCC 中诱导DKK1表达，并发现表皮生长因子受体 (EGFR) 的激活促进了平行的 MEK-ERK 和 PI3K-Akt 通路信号，这些信号汇聚到表观遗传刺激DKK1转录。在用 EGF 刺激的 HCC 细胞系中，EGFR 激活的 ERK 在 Ser ³⁷磷酸化激酶 PKM2 ，从而促进其核易位。同样在这些细胞中，EGFR 激活的 Akt 磷酸化了 Ser ¹⁸³⁴处的乙酰转移酶 p300. 随后，PKM2 和 p300 分别介导DKK1启动子处组蛋白 H3 的磷酸化和乙酰化，这协同增强了DKK1转录。该机制得到了细胞突变分析和大鼠化学诱导 HCC 模型的支持。研究结果表明，MEK 和 PI3K 通路的双重抑制可能会抑制DKK1的表达，从而抑制 HCC 患者的肿瘤转移。