Stabilization of C/EBPβ through direct interaction with STAT3 in H-Ras transformed human mammary epithelial cells.

Affiliation

Lee LL(1), Kim SJ(1), Hahn YI(2), Jang JH(1), Saeidi S(2), Surh YJ(3).
Author information:
(1)Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea.
(2)Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea.
(3)Tumor Microenvironment Global Core Research Center, College of Pharmacy, Seoul National University, Seoul, 08826, South Korea; Department of Molecular Medicine and Biopharmaceutical Sciences, Graduate School of Convergence Science and Technology, Seoul National University, Seoul, 08826, South Korea; Cancer Research Institute, Seoul National University, Seoul, 03080, South Korea. Electronic address: [Email]

Abstract

Signal transducer and activator of transcription 3 (STAT3) plays important roles in cancer-associated inflammation by controlling expression of proinflammatory cytokines and chemokines. Recent studies suggest that C/EBPβ (CCAAT-enhancer binding protein beta) and STAT3 synergistically stimulate cancer cell proliferation and epithelial-mesenchymal transition. C/EBPβ is a leucine-zipper transcription factor that regulates expression of a variety of inflammatory cytokines or chemokines, such as IL-8, G-CSF (granulocyte colony stimulating factor), and GM-CSF (granulocyte macrophage colony stimulating factor) which induce neutrophil infiltration and differentiation. However, molecular mechanisms by which STAT3 and C/EBPβ cooperatively interact had not been fully elucidated. In this study, we found that the level of C/EBPβ protein, but not that of its mRNA transcript, was decreased in the absence of STAT3 in H-Ras transformed human mammary epithelial (H-Ras MCF10A) cells. In addition, silencing STAT3 dramatically induced ubiquitination of C/EBPβ for proteasomal degradation. Furthermore, direct interaction between STAT3 and C/EBPβ was confirmed by immunoprecipitation and proximity ligation assays. Taken together, these results suggest that STAT3 stabilizes C/EBPβ, thereby promoting cancer-associated inflammation.