Abstract
Heme oxygenase-1 (HO-1) can promote tumor growth and reinforce the resistance of diffuse large B-cell lymphoma (DLBCL) cells to chemotherapeutic drug vincristine. We herein found that HO-1 protein expression was higher in high-risk DLBCL patients than in low-risk ones. Silencing HO-1 gene expression resisted vorinostat-induced apoptosis and arrested cell cycle in the G0/G1 phase of LY-10 cells. Western blot, co-immunoprecipitation and chromatin immunoprecipitation assays confirmed that the possible mechanisms may be increased cleaved caspase-3 protein expression, decreased phospho-histone deacetylase 3 protein expression, and activated histone acetylation of P27Kip1 promoter. Moreover, silencing HO-1 gene expression enhanced vorinostat-induced tumor cell apoptosis, prolonged survival time and promoted P27Kip1 protein expression in a xenograft mouse model.In conclusion, HO-1 is a potential therapeutic target of DLBCL. The findings provide a valuable preclinical evidence for sensitizing DLBCL patients with poor prognosis to histone deacetylase inhibitors.
Highlights
Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) that has a wide range of clinical presentations [1]
We demonstrated that Heme oxygenase-1 (HO-1) protein expression was positively correlated with International Prognostic Index (IPI) classification of ABC-diffuse large B-cell lymphoma (DLBCL) patients, and silencing HO-1 gene expression induced apoptosis and arrested cell cycle in the G0/G1 phase in ABC-DLBCL cell line LY-10 after SAHA treatment
HO-1 and HDAC3 protein expressions were higher in ABC-DLBCL than those in GCB-DLBCL
Summary
Diffuse large B-cell lymphoma (DLBCL) is an aggressive B-cell non-Hodgkin lymphoma (NHL) that has a wide range of clinical presentations [1]. In the post-rituximab era, the first-line therapy for DLBCL is a combination of rituximab, cyclophosphamide, doxorubicin, vincristine, and prednisone (R-CHOP) [3], and the outcomes of patients with DLBCL have been substantially improved (3-year estimate of eventfree survival was 67% in the R-CHOP group) [4]. Approximately 40% of patients are refractory to treatment or relapse after receiving current standard immunochemotherapy R-CHOP [5]. These refractory or relapsed DLBCL patients survive fewer than 5 years, and they have lower survival rates [6, 7]. Patients with ABC-DLBCL have poor outcomes compared with GCB-DLBCL patients (5-year overall survival, 35% vs 60%; P
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