PIASxα Ligase Enhances SUMO1 Modification of PTEN Protein as a SUMO E3 Ligase

Background: The activity of PTEN tumor suppressor is tightly controlled. Results: SUMOylation of PTEN enhanced by PIASx regulates PTEN activity. Conclusion: PIASx is a novel SUMO E3 ligase to promote SUMOylation of PTEN. Significance: PIASx-mediated SUMOylation of PTEN has a central role in tumor inhibition. The tumor suppressor PTEN plays a critical role in the regulation of multiple cellular processes that include survival, cell cycle, proliferation, and apoptosis. PTEN is frequently mutated or deleted in various human cancer cells to promote tumorigenesis. PTEN is regulated by SUMOylation, but the SUMO E3 ligase involved in the SUMOylation of PTEN remains unclear. Here, we demonstrated that PIASx is a SUMO E3 ligase for PTEN. PIASx physically interacted with PTEN both in vitro and in vivo. Their interaction depended on the integrity of phosphatase and C2 domains of PTEN and the region of PIASx comprising residues 134-347. PIASx enhanced PTEN protein stability by reducing PTEN ubiquitination, whereas the mutation of PTEN SUMO1 conjugation sites neutralized the effect of PIASx on PTEN protein half-life. Functionally, PIASx, as a potential tumor suppressor, negatively regulated the PI3K-Akt pathway through stabilizing PTEN protein. Overexpression of PIASx led to G(0)/G(1) cell cycle arrest, thus triggering cell proliferation inhibition and tumor suppression, whereas PIASx knockdown or deficiency in catalytic activity abolished the inhibition. Together our studies suggest that PIASx is a novel SUMO E3 ligase for PTEN, and it positively regulates PTEN protein level in tumor suppression.