Depletion of intracellular Ca²⁺ induces FOXM1 SUMOylation and accumulation on the inner nuclear membrane and accelerates G2/M cell cycle transition

Intracellular calcium (Ca²⁺) 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 Ca²⁺ on FOXM1 and found that Ca²⁺ 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 Ca²⁺ affects FOXM1, we found that among the posttranscriptional modifications, only SUMOylation of FOXM1 showed a pronounced increase under reduced Ca²⁺, and suppressed SUMOylation rescued FOXM1 sequestration. In addition, Ca²⁺-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 Ca²⁺ signaling and FOXM1 regulation, and we look to elucidate Ca²⁺-dependent FOXM1 SUMOylation-related biological functions in the future.