shRNA-dependent knockdown of RNF4 reduced RGMb mRNA levels and shRNA-mediated elimination of RNF4, or BMP6, or RGMb attenuated human osteosarcoma U-2-OS cell proliferation, and reduced their ability to form tumor spheres in culture as well as A375 melanoma cells (Fig. 4A–D and Supp. Here, RNF4 is linked to melanoma.