Abstract
Valproic acid (VPA) and suberoylanilide hydroxamic acid (SAHA) are both HDAC inhibitors (HDACi). Previous studies indicated that both inhibitors show therapeutic effects on acute myeloid leukaemia (AML), while the differential impacts of the two different HDACi on AML treatment still remains elusive. In this study, using 3-plex SILAC based quantitative proteomics technique, anti-acetyllysine antibody based affinity enrichment, high resolution LC-MS/MS and intensive bioinformatic analysis, the quantitative proteome and acetylome in SAHA and VPA treated AML HL60 cells were extensively studied. In total, 5,775 proteins and 1,124 lysine acetylation sites were successfully obtained in response to VAP and SAHA treatment. It is found that VPA and SAHA treatment differently induced proteome and acetylome profiling in AML HL60 cells. This study revealed the differential impacts of VPA and SAHA on proteome/acetylome in AML cells, deepening our understanding of HDAC inhibitor mediated AML therapeutics.
Highlights
suberoylanilide hydroxamic acid (SAHA) and Valproic acid (VPA) were both proved to be potential therapies for leucocythemia diseases
The biological process was firstly investigated (Fig. 2A), it is found that the up-regulated proteins in response to VPA and SAHA treatment shown very similar enrichment results such as hemostasis, leukocyte cell-cell adhesion and blood coagulation, showing that VPA and SAHA were with similar impacts on the proteome of HL60 cells
In VPA treatment, plasma lipoprotein particle, and transcription regulation related protein complexes including npBAP complex, nBAF complex, Brm-associated factor (BAF) type complex and SWI/SNF complex were enriched in the up-regulated proteins, while SAHA treatment induced many membrane and vesicular related cellular components which involved in multi organelles
Summary
SAHA and VPA were both proved to be potential therapies for leucocythemia diseases. SAHA was verified to have activity against leukemia and other hematologic malignancies in vitro experiments[17,18]. The clinic trial of SAHA in patients with advanced leukemias and myelodysplastic syndromes has been reported and some optimistic results had been observed[18,19]. The clinic trial of the therapeutic effect of VPA in combination with other small molecules such as decitabine and 5-azacytidine in leucocythemia treatment had been conducted[20,21,22]. The global proteome and lysine acetylome of AML HL60 cell lines in response to SAHA and VPA treatment were intensively studied by the combination of SILAC labeling, high-efficiency acetylation enrichment and high-resolution LC-MS/MS analysis (Fig. 1). We aimed to explore the mechanisms underlying the SAHA or VPA inhibited AML development, which may promote the clinical trial and even application of SAHA and VPA in the therapy of AML as well as other subtypes of leucocythemias
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