FBXW7-mediated stability regulation of signal transducer and activator of transcription 2 in melanoma formation
Menée sur des cellules de mélanome humain et à partir d'échantillons tumoraux, cette étude met en évidence le rôle de la régulation, par la protéine FBXW7, de la stabilité de la protéine STAT2 dans la prolifération des cellules cancéreuses et la croissance tumorale
The physiological relevance of STAT2 (a member of STAT family) in melanoma formation is clearly shown using a human skin tissue array. Moreover, FBXW7-mediated STAT2 protein stability regulation via ubiquitination is shown to play an essential role in melanoma cell proliferation in monolayer and anchorage-independent 3D culture systems. The molecular mechanisms that regulate STAT2 protein stability by FBXW7 include the interaction between CCD and DBD domains of STAT2 and the WD40 domain of FBXW7. STAT2 phosphorylation at the putative degron motifs that contain Ser381, Thr385, and Ser393 might be mediated by GSK3β. These serve as critical amino acids that form hydrogen bonds with the WD40 domain of FBXW7. Thus, the FBXW7–STAT2 signaling axis is an important target for melanoma treatment.In this study, we provide critical evidence that STAT2 stability regulation plays an essential role in melanoma cell proliferation and colony growth. We found that the interaction of FBXW7 and STAT2 induced STAT2 destabilization via a ubiquitination-mediated proteasomal degradation pathway. Notably, GSK3β-mediated STAT2 phosphorylation facilitated STAT2–FBXW7 interactions via the DNA binding domain of STAT2 and domains 1, 2, 6, and 7 of FBXW7 WD40. Importantly, the inverse correlation between protein levels of STAT2 and FBXW7 were observed not only in human melanoma cells but also in a human skin cancer tissue array. The relationship between protein levels of STAT2 and FBXW7, cell proliferation, and colony growth were similarly observed in the melanoma cell lines SK-MEL-2, -5, and -28. Moreover, STAT2 knockdown in melanoma cells suppressed melanoma cell proliferation and colony formation. These data demonstrated that FBXW7-mediated STAT2 stability regulation plays an essential role in melanoma cell proliferation and cancer growth.