Silencing heme oxygenase-1 increases the sensitivity of ABC-DLBCL cells to histone deacetylase inhibitor in vitro and in vivo
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Zhen Zhou1,2,3,5, Qin Fang4,5, Dan Ma1,2,3, Nana Zhe1,2, Mei Ren1,2, Bingqing Cheng1,2, Peifan Li1,2, Ping Liu1,2, Xiaojing Lin1,2, Sishi Tang1,2, Xiuying Hu1,2, Yudan Liao1,2, Yaming Zhang1,2, Tingting Lu1,2 and Jishi Wang1,2,3
1Department of Hematology, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
2Key Laboratory of Hematological Disease Diagnostic and Treatment Centre of Guizhou Province, Guiyang 550004, China
3Department of Hematology, Guizhou Provincial Laboratory of Hematopoietic Stem Cell Transplantation Center, Guiyang 550004, China
4Department of Pharmacy, Affiliated Hospital of Guizhou Medical University, Guiyang 550004, China
5Department of Pharmacy, Affiliated Baiyun Hospital of Guizhou Medical University, Guiyang 550004, China
Jishi Wang, email: [email protected]
Keywords: heme oxygenase-1, histone deacetylase 3, vorinostat, P27, diffuse large B-cell lymphoma
Received: July 22, 2016 Accepted: May 23, 2017 Published: July 28, 2017
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.
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