Fig. 5

The biological functions of STC2 under hypoxic conditions. STC2 promoter contains hypoxia response elements (HREs) and amino acid response elements (AAREs). Under hypoxic conditions, HIF-1α is stabilized, and forms the HIF-1 heterodimer through interacting with HIF-1β. Then, HIF-1 is translocated into the nucleus where it binds to CBP/p300 and form a transcription complex to induce the expression of STC2. In addition, hypoxia also induces the expression of ATF4 through increased gene transcription, protein translation and protein stabilization. Thereafter, ATF4 is translocated into nucleus and form a transcriptional complex with co-factors to enhance the expression of downstream genes; however, it remains elusive whether ATF4 also contributes to STC2 upregulation under hypoxic conditions. Functionally, STC2 promotes cell cycle progression through enhancing cyclin D expression and Rb phosphorylation; STC2 induces epithelial-mesenchymal transition (EMT) through upregulating mesenchymal markers (N-cadherin and vimentin) and downregulating E-cadherin; in addition, STC2 can drive cell migration and invasion through the upregulation of matrix metalloproteinase (MMP) -2 and -9