Oncogenic Human Papillomavirus 16E7 modulates SUMOylation of FoxM1b

Abstract

The oncogenic transcription factor Forkhead box M1b (FoxM1b), a key regulator of cell cycle, is often overexpressed in many human cancers. Interestingly, posttranslational modifications are known to play important role in regulating the levels and activity of FoxM1b. The purpose of the present study was to characterize the SUMOylation of FoxM1b and identify the functional consequences including viral pathogenesis. Here, we report that FoxM1b interacts with SUMOylating enzymes Ubc9 and PIAS1 and acts as a substrate for SUMOylation. We also show that SUMOylation facilitates FoxM1b protein destabilization and nucleocytoplasmic shuttling. More importantly, we provide the first evidence for a role of E7 oncoprotein in high risk human papillomavirus (HPV) mediated upregulation of FoxM1b. The elevated expression of FoxM1 was determined to be posttranscriptional and was attributed to decreased SUMOylation of FoxM1b in the E7-expressing cells. Moreover, we demonstrate the involvement of SUMOylation in regulation of FoxM1 and present biochemical evidence that HPV16 E7 oncoprotein can modulate SUMOylation of FoxM1b by impairing its interaction with Ubc9. Together, these results provide a novel connection between SUMOylation of FoxM1b and HPV carcinogenesis. The findings may have important implications in the discovery of future anti-cancer therapeutics.