MeCP2 drives hepatocellular carcinoma progression via enforcing HOXD3 promoter methylation and expression through the HB-EGF/EGFR pathway.

Homeobox D3 (HOXD3), a member of the homeobox family, was described to regulate tumorigenesis, invasion, metastasis, and angiogenesis in various tumor types. However, the molecular mechanisms regulating HOXD3 during hepatocellular carcinoma (HCC) migration, invasion, and angiogenesis remain elusive. In this study, we demonstrated that HOXD3 expression is enhanced by the binding of methyl-CpG-binding protein 2 (MeCP2), a methyl-CpG binding protein, together with CREB1to the hypermethylated promoter of HOXD3. Inhibition of HOXD3 eliminated the tumorigenic effects of MeCP2 on HCC cells. Furthermore, HOXD3 directly targeted the promoter region of heparin-binding epidermal growth factor (HB-EGF) via the EGFR-ERK1/2 cell signaling pathway and promoted invasion, metastasis, and angiogenesis of HCC in vitro and in vivo. Additionally, elevated expression of MeCP2, CREB1, and HB-EGF in HCC correlated with a poor survival rate. Our findings reveal the function of the MeCP2/HOXD3/HB-EGF regulatory axis in HCC, rendering it an attractive candidate for the development of targeted therapeutics and as a potential biomarker in patients with HCC.