The current concept in the cell cycle stipulates that constant synthesis without coupled ubiquitin- mediated proteolysis maintains the levels of cyclin-dependent kinase proteins through the cell cycle. CDK proteins are elevated in glioblastoma, which has long been thought due to gene amplifications, although the amplifications occur only in a small set of the tumors according to the genome.

In this study, we show that the G1 phase CDK6 is a substrate of both ubiquitin and small ubiquitin-like modifier-1 (SUMO1), and that CDK6 is sumoylated due to the elevated activity of SUMO1 conjugation in glioblastoma. CDK6 sumoylation at Lys 216 structurally blocks the access of ubiquitination molecules to the Lys 147 ubiquitination site; thus, CDK6 sumoylation stabilize the protein, maintains the kinase activity and drives the cell cycle through G1/S transition. Inhibition of SUMO1 conjugation causes G1 arrest and abolishes the self-renewal and tumorigenic property of glioblastoma initiating or stem cells. In conclusion, SUMO1-CDK6 conjugation constitutes a new mechanism of cell cycle control and selective inhibition of SUMO1 conjugation may provide a novel strategy for the development of the cancer stem cells-targeted treatment.