Depletion of intracellular Ca induces FOXM1 SUMOylation and accumulation on the inner nuclear membrane and accelerates G2/M cell cycle transition.

Intracellular calcium (Ca) has been reported to regulate transcription factor activity and cancer development, but how it affects the function of Forkhead box protein M1 (FOXM1), a crucial transcription factor and key oncogene participating in tumorigenesis, remains unclear. Here, we investigated the regulatory role of Ca on FOXM1 and found that Ca depletion caused the distribution of FOXM1 to aggregate on the nuclear envelope, which was also observed in many cell lines. Further experiments revealed that sequestrated FOXM1 colocalized with lamin B in the inner nuclear membrane (INM) and was affected by the activity of nuclear export protein exportin 1 (XPO1). To investigate how intracellular Ca affects FOXM1, we found that among the posttranscriptional modifications, only SUMOylation of FOXM1 showed a pronounced increase under reduced Ca, and suppressed SUMOylation rescued FOXM1 sequestration. In addition, Ca-dependent SUMOylated FOXM1 appeared to enhance the G2/M transition of the cell cycle and decrease cell apoptosis. In conclusion, our findings provide a molecular basis for the relationship between Ca signaling and FOXM1 regulation, and we look to elucidate Ca-dependent FOXM1 SUMOylation-related biological functions in the future.