SMAD6 induces ubiquitin-mediated degradation of PIAS3 in GBM cells to enhance STAT3-mediated proliferation and stem-like cell initiation, whereas TRIM8 represses PIAS3 through a similar mechanism to maintain STAT3-mediated stemness and self-renewal of GBM stem-like cells. The gene discussed is STAT3; the disease is glioblastoma.