Abstract
Acute myeloid leukemia (AML) is recognized as a complex disease of hematopoietic stem cell disorders, but its pathogenesis mechanisms, diagnosis, and treatment remain unclear. General histone deacetylase (HDAC) inhibitors have been used in blood cancers including AML, but the lack of gene specificity greatly limits their anti-cancer effects and clinical applications. Here, we found that HDAC1 expression was negatively correlated with that of Krüppel-like factor 4 (Klf4) and that AML patients with lower HDAC1 level had better prognosis. Further, knockdown of HDAC1 in leukemia cells K562, HL-60, and U937 significantly increased Klf4 expression and inhibited cell cycle progression and cell proliferation, similar results were found for HDAC inhibitors (VPA and mocetinostat). Moreover, overexpression or knockdown of Klf4 could markedly block the effects of HDAC1 overexpression or knockdown on leukemia cells in vitro and in vivo, respectively. Mechanistic analyses demonstrated that HDAC1 and Klf4 competitively bound to the promoter region of Klf4 and oppositely regulated Klf4 expression in myeloid leukemia. We identified HDAC1 as a potential specific target for repressing cell proliferation and inducing cell cycle arrest through interplay and modulation of Klf4 expression, suggests that HDAC1 and Klf4 are potential new molecular markers and targets for clinical diagnosis, prognosis, and treatment of myeloid leukemia.
Highlights
Multiple studies have demonstrated that Acute myeloid leukemia (AML) cells may exhibit several genetic and epigenetic lesions.[4]
These findings indicate that the negative correlation between HDAC1 and Klf[4] may have a critical role in the genesis of human leukemia
Dualluciferase reporter gene assay confirmed that Klf[4] could bind at the promoter regions of p27 (Supplementary Figure S4D). All of these results indicate that HDAC1 knockdown inhibits cell proliferation mainly through Klf[4] activation, direct binding of Klf[4] to p21 and p27 promoter regions, and the knockdown enhanced the binding of Klf[4] at its own promoter regions (Figure 4d), which indicates that HDAC1 and Klf[4] may compete in binding at the Klf[4] promoter region
Summary
Multiple studies have demonstrated that AML cells may exhibit several genetic and epigenetic lesions.[4]. Klf[4] has been identified as a tumor-suppressor gene in colon, bladder, and gastric cancers.[15,16,17,18] Other studies have demonstrated that Klf[4] is an oncogene in breast cancer and skin carcinoma.[19,20] As a novel anti-hypertrophic transcriptional regulator, Klf[4] mediates the HDACi-induced prevention of cardiac hypertrophy.[21,22] Activated HDAC2 triggers hypertrophy by inhibiting the signal cascades of either Klf[4] or inositol polyphosphate-5-phosphatase f (Inpp5f), indicating that Klf[4] might be a specific target of certain HDACs. Recently, evidence has suggested that Klf[4] may serve as a tumor suppressor in leukemia.[23,24] Previous studies have demonstrated that Klf[4] is repressed by CDX2 in AML and colon cancer,[25] and downregulation of Klf[4] by Jak[2] allows for increased proliferation of progenitor cells.[26] the exact role of Klf[4] and HDACs in leukemia, in AML, is unclear. By evaluating the effects of specific HDACs in human myeloid leukemia, we first found that the expression level of
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