SUMOylation of HMGA2: selective destabilization of promyelocytic leukemia protein via proteasome

Abstract

The HMGA2 architectural protein functions in a variety of cellular processes, such as cell growth, transcription regulation, neoplastic transformation, and progression. Up-regulation of HMGA2 protein is observed in many tumors and is associated with advanced cancers with poor prognoses. Although the expression and biochemical properties of HMGA2 protein are regulated by microRNA and phosphorylation, it is unknown whether HMGA2 activity can also be regulated by SUMOylation, and that is what is investigated in this report. We identified HMGA2 as a SUMOylation target and showed that the expression of wild-type HMGA2, but not SUMOylation-defective HMGA2(2K/R), selectively lowered the steady-state level of PML protein. Consequently, the HMGA2-elicited PML down-regulation rendered a reduction in the average number of PML nuclear bodies per cell and the volume of PML assembled per PML nuclear body. Using small interfering RNA to suppress endogenous ubiquitin expression and proteasome inhibitor to repress ubiquitin-mediated protein degradation, we showed that HMGA2 confers PML down-regulation through ubiquitin-proteasomedependent protein degradation. Importantly, arsenic trioxide treatment stimulated HMGA2 SUMOylation, leading to the formation of HMGA2 nuclear foci surrounding PML nuclear bodies and the stimulation of PML degradation.Collectively, our results unveil a previously unrecognized effect by HMGA2 on the modulation of PML protein level, providing a novel mechanism underlying HMGA2 function and underscoring the molecular basis for oncogenic progression by HMGA2. [Mol Cancer Ther 2008;7(4):923-34]

High Mobility Group Nucleosomal Binding Domain 2 (HMGN2) SUMOylation by the SUMO E3 Ligase PIAS1 Decreases the Binding Affinity to Nucleosome Core Particles

“…Recently, it was reported that HMGA2 can be SUMOylated and that its SUMOylation is required to destabilize promyelocytic leukemia protein (21). In addition, Xenopus HMGB3 can be SUMOylated when it is overexpressed in the cell.…”

HMG modifications and nuclear function

“…Aside from phosphorylation, a study by Cao et al [62] showed that HMGA2 protein can undergo SUMOylation, which can lead to the degradation of promyelocytic leukemia (PML) protein via the ubiquitin-proteasomal pathway; interestingly, arsenic trioxide treatment can stimulate the SUMOylation of HMGA2 and the subsequent degradation of PML.…”

Regulation of apoptosis by PML and the PML-NBs

“…Finally, another group has recently found that HMGA2, a member of a family of architectural proteins and regulators of gene transcription, also promotes PML degradation by the proteasome (Cao et al, 2008). Intriguingly, sumoylation is again brought into the picture because only sumoylated HMGA2 can promote PML degradation (Cao et al, 2008).…”

“…Intriguingly, sumoylation is again brought into the picture because only sumoylated HMGA2 can promote PML degradation (Cao et al, 2008). Furthermore, arsenic trioxide stimulates HMGA2 sumoylation and the localization of HMGA2 in rings that surround PML-NBs (Cao et al, 2008).…”