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

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 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 4E-BP1, and the attenuation of cell proliferation was enhanced by the expression of an mTORC1-mediated phosphorylation-defective mutant of 4E-BP1. Chromatin immunoprecipitation and promoter mapping using a luciferase reporter assay showed that the -951-bp 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.