The promyelocytic
leukemia (PML)
protein is a
tumor suppressor originally identified in
acute promyelocytic leukemia and implicated in
tumorigenesis in multiple forms of
cancer. Here, we demonstrate that the PML
protein undergoes ubiquitination-mediated degradation facilitated by an
E3 ligase UHRF1 (
ubiquitin-like with PHD and RING finger domains 1), which is commonly upregulated in various human
malignancies. Furthermore, UHRF1 negatively regulates PML
protein accumulation in primary human umbilical vein endothelial cells (HUVECs), HEK 293 cells and
cancer cells. Knockdown of UHRF1 upregulates whereas ectopic overexpression of UHRF1 downregulates
protein abundance of endogenous or exogenous PML, doing so through its binding to the N-terminus of PML. Overexpression of wild-type UHRF1 shortens PML
protein half-life and promotes PML polyubiquitination, whereas deletion of the RING domain or coexpression of the dominant-negative
E2 ubiquitin-conjugating enzyme, E2D2, attenuates this modification to PML. Finally, knockdown of UHRF1 prolongs PML half-life and increases PML
protein accumulation, yet inhibits cell migration and in vitro capillary tube formation, whereas co-knockdown of PML compromises this inhibitory effect. These findings suggest that UHRF1 promotes the turnover of PML
protein, and thus targeting UHRF1 to restore PML-mediated
tumor suppression represents a promising, novel, anticancer strategy.