Histone deacetylase 3 preferentially binds and collaborates with the transcription factor RUNX1 to repress AML1–ETO–dependent transcription in t(8;21) AML

Abstract

In up to 15% of acute myeloid leukemias (AMLs), a recurring chromosomal translocation, termed t(8;21), generates the AML1–eight–twenty-one (ETO) leukemia fusion protein, which contains the DNA-binding domain of Runt-related transcription factor 1 (RUNX1) and almost all of ETO. RUNX1 and the AML1–ETO fusion protein are coexpressed in t(8;21) AML cells and antagonize each other's gene-regulatory functions. AML1–ETO represses transcription of RUNX1 target genes by competitively displacing RUNX1 and recruiting corepressors such as histone deacetylase 3 (HDAC3). Recent studies have shown that AML1–ETO and RUNX1 co-occupy the binding sites of AML1–ETO–activated genes. How this joined binding allows RUNX1 to antagonize AML1–ETO–mediated transcriptional activation is unclear. Here we show that RUNX1 functions as a bona fide repressor of transcription activated by AML1–ETO. Mechanistically, we show that RUNX1 is a component of the HDAC3 corepressor complex and that HDAC3 preferentially binds to RUNX1 rather than to AML1–ETO in t(8;21) AML cells. Studying the regulation of interleukin-8 (IL8), a newly identified AML1–ETO–activated gene, we demonstrate that RUNX1 and HDAC3 collaboratively repress AML1–ETO–dependent transcription, a finding further supported by results of genome-wide analyses of AML1–ETO–activated genes. These and other results from the genome-wide studies also have important implications for the mechanistic understanding of gene-specific coactivator and corepressor functions across the AML1–ETO/RUNX1 cistrome.

A single amino acid at PNT domain of ERG mediates its leukemogenic activity through interaction with the NCoR-HDAC3 co-repressor complex

“…ChIP-qPCR after knockdown of ERG revealed an increase in P300 and a decrease in HDAC1 occupancy at the promoter region of RUNX1-RUNX1T1 25 . Furthermore, a recent study has demonstrated that RUNX1 is a component of the NCoR-HDAC3 complex in t(8;21) AML and collaboratively represses RUNX1-RUNX1T1-dependent transcription, thereby linking HDAC3 directly to leukemogenesis associated with t(8;21) 62 . Taken together, the enhanced apoptosis observed in SKNO1 cells following HDAC3 inhibition could be explained by a co-regulatory function of ERG and the NCoR-HDAC3 complex in t(8;21) leukemic cells.…”

Antihyperlipidemic Activity of Gut-Restricted LXR Inverse Agonists

“…The FASTQ files were aligned to the mm10 mouse reference genome and subsequently analyzed using HOMER software, as previously described. 40 Cell Culture and Luciferase Assays. HepG2 cells were purchased from ATCC and maintained in Gibco Advanced MEM media supplemented with 10% FBS (Gemini Bio) and L-glutamine (Gibco) at 37 °C with 5% CO 2 , as previously described.…”

Roles of Histone Deacetylases in Acute Myeloid Leukemia With Fusion Proteins

“…Inhibition of HDAC1 and HDAC2 leads to down-regulation of RAD51, BRCA1, and CHK1, which are crucial for the DNA damage response (DDR) and subsequent DNA double-strand break and apoptosis in AML cell lines. And AML-1-ETO can bind with HDAC1, 2, and 3 to repress the AML1 target genes in t (8,21) AML ( 123 ). And HDAC6 deacetylates the chaperone Hsp90, eliciting the interaction with AML1-ETO protein, which can be dissociated by HDAC inhibitors that mediates the degradation of AML1-ETO protein.…”