Fbw7 regulates apoptosis in activated B-cell like diffuse large B-cell lymphoma by targeting Stat3 for ubiquitylation and degradation

Background: the ubiquitin-ligase fbw7 acts as a tumor suppressor,targeting lots of proto-oncogenes for proteolysis. however,the exact role of fbw7 in diffuse large b-cell lymphoma (dlbcl) development remains unclear. methods: we evaluated fbw7 expression in patient samples of dlbcl using immunohistochemical staining. the effect of fbw7 overexpression on cell viability and apoptosis was investigated using activated b-cell (abc) like dlbcl cell lines. the mechanism of fbw7 activity in dlbcl was investigated using immunoprecipitation,ubiquitination,western blot and qualitative analyses. results: the non-germinal center b-cell-like subtype of dlbcl showed reduced fbw7 expression compared with the germinal center b-cell (gbc) subtype,and low fbw7 expression was associated with a worse prognosis. fbw7 overexpression caused decreased cell viability and increased apoptosis rates in the abc-dlbcl cell lines su-dhl-2 and oci-ly-3. importantly,stat3 and phospho-stat3tyr705 stability were reduced following fbw7 overexpression in abc-dlbcl cell lines. in hek293t and su-dhl-2 cells,we demonstrated that fbw7 interacts with stat3 and pstat3tyr705 to regulate their ubiquitylation and degradation. downstream anti-apoptotic target genes of activated stat3,including myc,survivin,mcl-1,pim-1,bcl-2 and bcl-xl showed decreased mrna expression following exogenous fbw7 overexpression. the negative relationship between fbw7 and pstat3tyr705 levels was also confirmed in dlbcl patient samples. conclusion: the ubiquitin-ligase fbw7 mediates apoptosis through targeting stat3 for ubiquitylation and degradation in abc-dlbcl. thus,our study may offer a promising approach for abc-dlbcl therapy through stat3 inhibition. © 2017 the author(s).