STAT3‐mediated MLST8 gene expression regulates cap‐dependent translation in cancer cells

Abstract

Signal transducer and activator of transcription 3 (STAT3) regulates cell growth, cell survival, angiogenesis, metastasis of cancer cells, and cancer immune evasion by regulating gene expression as a transcription factor. However, the effect of STAT3 on translation is almost unknown. We demonstrated that STAT3 acts as a trans‐acting factor for MLST8 gene expression and the protein level of mLST8, a core component of mechanistic target of rapamycin complex 1 and 2 (mTORC1/2), positively regulates the mTORC1/2 downstream pathways. Suppression of STAT3 by siRNA attenuated 4E‐BP1 phosphorylation, cap‐dependent translation, and cell proliferation in a variety of cancer cells. In HCT116 cells, STAT3 knockdown‐induced decreases in 4E‐BP1 and AKT phosphorylation levels were further attenuated by MLST8 knockdown or recovered by mLST8 overexpression. STAT3 knockdown‐induced G2/M phase arrest was partially restored by co‐knockdown of 4EBP1, and the attenuation of cell proliferation was enhanced by the expression of an mTORC1‐mediated phosphorylation‐defective mutant of 4E‐BP1. ChIP and promoter mapping using a luciferase reporter assay showed that the −951 to −894 bp of MLST8 promoter seems to include STAT3‐binding site. Overall, these results suggest that STAT3‐driven MLST8 gene expression regulates cap‐dependent translation through 4E‐BP1 phosphorylation in cancer cells.

Keywords

• 4E‐BP1
• cross‐talk
• MLST8
• mTORC1
• STAT3