The activity of the EMT suppressor GRHL2 is regulated by SUMOylation

The developmental transcription factor grainyhead-like 2 (GRHL2) has been attributed both tumor-suppressive and protumorigenic functions in a large variety of human cancers. Despite its fundamental role in cancer development and progression, mechanisms modulating expression or activity of GRHL2 in cancer cells still remain elusive. We identified several components of the SUMOylation machinery as candidate GRHL2 interactors using a yeast two-hybrid screening approach and a single major GRHL2 SUMOylation site at lysine residue 159. SUMOylation of GRHL2 at lysine 159 enhances its transcriptional activity and was found to be stimulated by phosphorylation of GRHL2 at threonine 164 by p38α/β MAPKs or by interaction with members of the PIAS family of SUMO E3 ligases. Additionally, structural analysis identified GRHL2 as an intrinsically disordered protein with a high propensity to misfold and to form aggresome-like structures in the nucleus, resulting in repression of GRHL2 transcriptional activity. Results obtained by immunohistochemical analysis of GRHL2 expression in primary breast cancers support an important role of GRHL2 subnuclear compartmentalization in breast carcinogenesis. Taken together, our results provide new insights into complex regulatory mechanisms governing GRHL2 activity in cancer cells.