Low expression of GFI-1 Gene is associated with Panobinostat-resistance in acute myeloid leukemia through influencing the level of HO-1
| Autor: | Danna Wei, Sishi Tang, Nana Zhe, Qin Fang, Tingting Lu, Jishi Wang, Bingqing Cheng, Dan Ma, Zheng Zhou, Kunlin Yu |
|---|---|
| Rok vydání: | 2018 |
| Předmět: |
Adult
Male 0301 basic medicine Indoles Adolescent Antineoplastic Agents HL-60 Cells Hydroxamic Acids Young Adult 03 medical and health sciences chemistry.chemical_compound 0302 clinical medicine Panobinostat Humans Medicine Epigenetics Protein kinase B PI3K/AKT/mTOR pathway Aged Pharmacology Histone deacetylase 2 business.industry Myeloid leukemia General Medicine Middle Aged HDAC3 HDAC1 DNA-Binding Proteins Gene Expression Regulation Neoplastic Leukemia Myeloid Acute 030104 developmental biology chemistry Drug Resistance Neoplasm 030220 oncology & carcinogenesis Cancer research Female business Heme Oxygenase-1 Transcription Factors |
| Zdroj: | Biomedicine & Pharmacotherapy. 100:509-520 |
| ISSN: | 0753-3322 |
| DOI: | 10.1016/j.biopha.2018.02.039 |
| Popis: | To improve the treatment outcomes of acute myeloid leukemia (AML), epigenetic modification has been widely tested and used in recent years. However, drug-resistance is still a choke point to cure the malignancy. The growth factor independent 1 transcriptional repressor (GFI-1), as a zinc-finger transcriptional repressor, can bind histone deacetylases to allow the transcriptional repression. According to the finding of our study, AML patients with low level of GFI-1 not only implicated poor prognosis but also caused Panobinostat-resistance. In our prevent study revealed that heme oxygenase-1(HO-1) was one of the main factors leading to chemotherapy sensitivity to AML. Thus, this study tried to test the correlation between GFI-1 and HO-1. Our study discovered that AML patients with lower expression of GFI-1 had higher level of HO-1, HDAC1, HDAC2 and HDAC3, which resulted in poor prognosis in AML. The results of the in vitro study were the same. Panobinostat is a promising new class of anti-cancer drugs in AML. However, knocking down GFI-1 by siRNA could eliminate the Panobinostat-induced cell apoptosis. Subsequently, we utilized ZnPP to down regulate the level of HO-1, finding that the Panobinostat-resistance between the low level of GFI-1 and empty vector had eased. After further exploring the mechanism, it could be found that with knock down GFI-1, the phosphorylation of Akt and PI3K could be activated. Subsequently, Akt pathway and HO-1 inhibitor were utilized respectively and the resistance was reversed. It suggested that the resistance of Panobinostat to AML cells at low level of GFI-1 was mainly due to up-regulated level of HO-1 through the PI3K-Akt pathway. |
| Databáze: | OpenAIRE |
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