HO-1 promotes resistance to an EZH2 inhibitor through the pRB-E2F pathway: correlation with the progression of myelodysplastic syndrome into acute myeloid leukemia.
机构：[1]Department of Hematology, Hematological Institute of Guizhou Province,Guizhou Provincial Laboratory of Hematopoietic Stem Cell TransplantationCentre, Affiliated Hospital of Guizhou Medical University, Guiyang 550004,Guizhou, People’s Republic of China[2]Department of Pharmacy, The AffiliatedHospital of Guizhou Medical University, Guiyang, People’s Republic of China[3]Clinical Medicine Research Center of Affiliated Hospital of Guizhou MedicalUniversity, Guiyang, Guizhou, People’s Republic of China[4]Intensive Care Unit,Affiliated Hospital of North Sichuan Medical College, Nanchong, Sichuan,People’s Republic of China[5]Department of Hematology, Affiliated Hospitalof North Sichuan Medical College, Nanchong, Sichuan, People’s Republicof China
Myelodysplastic syndrome (MDS) can progress to acute myeloid leukemia (AML), and conventional chemotherapy (decitabine) does not effectively inhibit tumor cells. Enhancer of zeste homologue 2 (EZH2) and Heme oxygenase-1 (HO-1) are two key factors in patients resistance and deterioration.
In total, 58 MDS patients were divided into four groups. We analyzed the difference in HO-1 and EZH2 expression among the groups by real-time PCR. After treatment with Hemin or Znpp IX, flow cytometry was used to detect apoptosis and assess the cell cycle distribution of tumor cells. Following injection of mice with very high-risk MDS cells, spleen and bone marrow samples were studied by immunohistochemistry (IHC) and hematoxylin and eosin (H&E) staining. MDS cells overexpressing EZH2 and HO-1 were analyzed by high-throughput sequencing. The effect of HO-1 on the pRB-E2F pathway was analyzed by Western blotting. The effects of decitabine on P15INK4B and TP53 in MDS cells after inhibiting HO-1 were detected by Western blotting.
Real-time PCR results showed that EZH2 and HO-1 expression levels were higher in MDS patients than in normal donors. The levels of HO-1 and EZH2 were simultaneously increased in the high-risk and very high-risk groups. Linear correlation analysis and laser scanning confocal microscopy results indicated that EZH2 was related to HO-1. MDS cells that highly expressed EZH2 and HO-1 infiltrated the tissues of experimental mice. IHC results indicated that these phenomena were related to the pRB-E2F pathway. High-throughput sequencing indicated that the progression of MDS to AML was related to EZH2. Using the E2F inhibitor HLM006474 and the EZH2 inhibitor JQEZ5, we showed that HO-1 could regulate EZH2 expression. HO-1 could stimulate the transcription and activation of EZH2 through the pRB-E2F pathway in MDS patients during chemotherapy, which reduced TP53 and P15INK4B expression.
EZH2 was associated with HO-1 in high-risk and very high-risk MDS patients. HO-1 could influence MDS resistance and progression to AML.
基金：
National Natural Science Foundation
of China (#81360501, #81470006, and #81660616), the International
Cooperation Project of Guizhou Province (#2011-7010), the Social Project of
Guizhou Province (#2011-3012), and the Provincial Governor Special Fund of
Guizhou Province (#2010-84).
语种：
外文
PubmedID：
中科院(CAS)分区：
出版当年[2019]版：
大类|2 区医学
小类|3 区医学：研究与实验
最新[2023]版：
大类|2 区医学
小类|2 区医学：研究与实验
第一作者：
第一作者机构：[1]Department of Hematology, Hematological Institute of Guizhou Province,Guizhou Provincial Laboratory of Hematopoietic Stem Cell TransplantationCentre, Affiliated Hospital of Guizhou Medical University, Guiyang 550004,Guizhou, People’s Republic of China
通讯作者：
推荐引用方式(GB/T 7714)：
He Zhengchang,Zhang Siyu,Ma Dan,et al.HO-1 promotes resistance to an EZH2 inhibitor through the pRB-E2F pathway: correlation with the progression of myelodysplastic syndrome into acute myeloid leukemia.[J].Journal of translational medicine.2019,17(1):366.doi:10.1186/s12967-019-2115-9.
APA：
He Zhengchang,Zhang Siyu,Ma Dan,Fang Qin,Yang Liping...&Wang Jishi.(2019).HO-1 promotes resistance to an EZH2 inhibitor through the pRB-E2F pathway: correlation with the progression of myelodysplastic syndrome into acute myeloid leukemia..Journal of translational medicine,17,(1)
MLA：
He Zhengchang,et al."HO-1 promotes resistance to an EZH2 inhibitor through the pRB-E2F pathway: correlation with the progression of myelodysplastic syndrome into acute myeloid leukemia.".Journal of translational medicine 17..1(2019):366
医学