HDAC8 promotes daunorubicin resistance of human acute myeloid leukemia cells via regulation of IL-6 and IL-8

Abstract

The chemoresistance is one of the major challenges for acute myeloid leukemia (AML) treatment. We found that the expression of histone deacetylase 8 (HDAC8) was increased in daunorubicin (DNR) resistant AML cells, while targeted inhibition of HDAC8 by its specific siRNA or inhibitor can restore sensitivity of DNR treatment . Further, targeted inhibition of HDAC8 can suppress expression of interleukin 6 (IL-6) and IL-8. While recombinant IL-6 (rIL-6) and rIL-8 can reverse si-HDAC8-resored DNR sensitivity of AML cells. Mechanistical study revealed that HDAC8 increased the expression of p65, one of key components of NF-κB complex, to promote the expression of IL-6 and IL-8. It might be due to that HDAC8 can directly bind with the promoter of p65 to increase its transcription and expression. Collectively, our data suggested that HDAC8 promotes DNR resistance of human AML cells via regulation of IL-6 and IL-8.

The potential regulatory role of the lncRNA-miRNA-mRNA axis in teleost fish

“…LncRNAANAPC2 and lncRNA-NEFM interact with miR-451 to target histone deacetylase 8 (hdac8) and natriuretic peptide receptor 2 (npr2) ( 87 ). These network targeting genes tnfaip2, jnk, cc7, glut3, npr2 and hdac8 were all proven to induce inflammatory responses associated with the NF-kB or MAPK pathway ( 56 , 60 , 61 , 71 , 88 ). These data suggest that the lncRNA-miRNA-mRNA networks mediated by lncRNA-WAS, lncRNA-C8807, lncRNA-SUMO3, lncRNA-HDMO13, lncRNAANAPC2 and lncRNA-NEFM play positive regulatory roles in the inflammatory response of grass carp to A. hydrophila challenge.…”

The role of protein acetylation in carcinogenesis and targeted drug discovery

“…Aberrant expression of HDACs has also been shown to correlate with tumor resistance. HDAC8 increases the expression of p65, a key component of the NF-κB complex, and promotes the expression of IL-6 and IL-8 ( 103 ). This may be because HDAC8 can directly bind to the promoter of p65, increasing its transcription and expression.…”

“…This may be because HDAC8 can directly bind to the promoter of p65, increasing its transcription and expression. Thus, HDAC8 promotes DNR resistance in human AML cells by regulating IL-6 and IL-8 ( 103 ).…”

Structure-Based Discovery of Selective Histone Deacetylase 8 Degraders with Potent Anticancer Activity

“…Histone/protein deacetylase (HDAC) enzymes are involved in the epigenetic regulation of gene expression and the cell cycle. , There are 18 HDAC family members that are categorized into two groups: (1) NAD+-dependent sirtuins (SIRT1-7) and zinc-dependent enzymes (HDAC1–11) and (2) metal-dependent HDACs, which can be further divided into three classes. − Histone deacetylase 8 (HDAC8) is a class I HDAC that is ubiquitously expressed and located in both the nucleus and cytoplasm of cells. , HDAC8 is upregulated in aggressive colon, lung and pancreatic cancers, acute lymphocytic leukemia, acute myeloid leukemia, and childhood neuroblastoma. − Its expression is regulated by the lipogenic transcription factor sterol regulatory element binding protein-1 (SREBP1) and the SOX-family of transcription factors. , Recent analyses of breast cancer tissues have indicated that hypomethylation of the HDAC8 promoter and HDAC8 overexpression are associated with disease progression and an overall poor prognosis . Moreover, inhibiting HDAC8 activity or expression has been shown to induce apoptosis in T-cell lymphomas and inhibit tumor cell proliferation in human lung, colon, leukemia, gastric adenocarcinoma, and cervical cancer cell lines. , Thus, as an epigenetic regulator involved in these pathways, HDAC8 represents an important therapeutic target for various cancers. , HDAC8 also has a crucial non-canonical scaffolding function and interacts with transcription factors to control the expression of several genes. , …”