WDR5 Supports an N-Myc Transcriptional Complex That Drives a Protumorigenic Gene Expression Signature in Neuroblastoma

Abstract

MYCN gene amplification in neuroblastoma drives a gene expression program that correlates strongly with aggressive disease. Mechanistically, trimethylation of histone H3 lysine 4 (H3K4) at target gene promoters is a strict prerequisite for this transcriptional program to be enacted. WDR5 is a histone H3K4 presenter that has been found to have an essential role in H3K4 trimethylation. For this reason, in this study, we investigated the relationship between WDR5-mediated H3K4 trimethylation and N-Myc transcriptional programs in neuroblastoma cells. N-Myc upregulated WDR5 expression in neuroblastoma cells. Gene expression analysis revealed that WDR5 target genes included those with MYC-binding elements at promoters such as MDM2. We showed that WDR5 could form a protein complex at the MDM2 promoter with N-Myc, but not p53, leading to histone H3K4 trimethylation and activation of MDM2 transcription. RNAi-mediated attenuation of WDR5 upregulated expression of wild-type but not mutant p53, an effect associated with growth inhibition and apoptosis. Similarly, a small-molecule antagonist of WDR5 reduced N-Myc/WDR5 complex formation, N-Myc target gene expression, and cell growth in neuroblastoma cells. In MYCN-transgenic mice, WDR5 was overexpressed in precancerous ganglion and neuroblastoma cells compared with normal ganglion cells. Clinically, elevated levels of WDR5 in neuroblastoma specimens were an independent predictor of poor overall survival. Overall, our results identify WDR5 as a key cofactor for N-Myc-regulated transcriptional activation and tumorigenesis and as a novel therapeutic target for MYCN-amplified neuroblastomas. Cancer Res; 75(23); 5143-54. Ó2015 AACR.

In Vivo Functional Platform Targeting Patient-Derived Xenografts Identifies WDR5-Myc Association as a Critical Determinant of Pancreatic Cancer

“…The analysis of the chromatin-bound fraction also highlighted a reduction in c-Myc as a consequence of WDR5 silencing. The recent exciting finding of a direct interaction between WDR5 and c-Myc could imply that WDR5 may be recruited to chromatin to execute on Myc-dependent functions in replication (Thomas et al, 2015;Sun et al, 2015). By performing immunoprecipitation experiments for exogenously expressed Flag-WDR5 or endogenous c-Myc we confirmed the physical interaction of these two proteins in PDAC cells ( Figure 6F).…”

Hijacking a key chromatin modulator creates epigenetic vulnerability for MYC-driven cancer

“…On the other hand, genetic mutations of the core subunits are rarely found in human cancers. Instead, the DPY30 (51), ASH2L (24,52), and WDR5 (25,53,54) core subunits have been found to be overexpressed in cancers, show correlation of high expression levels with poor prognosis, and, in some cases, functionally promote tumorigenesis. Such differential regulations and roles elicit interesting questions relating to the exact roles of these subunits and the associated H3K4 methylation in cancer and merit further investigation.…”

WDR5 high expression and its effect on tumorigenesis in leukemia

“…It is reported that WDR5 drives the expression of protumorigenic gene-MDM2 with c-MYC in neuroblastoma [35]; WDR5 high expression promotes proliferation, self-renewal and chemoresistance in bladder cancer via mediating H3K4 trimethylation on cell cycle genes such as CCNA, CCNB1, CCND1, CCNE1 etc. [36]; Also it has reports that blocking of MLL-WDR5 interaction and MLL1 knockdown induced the suppression of c-MYC and BCL-2 in leukemia cells [27]; and loss of WDR5 increases expression of G-CSF, ccl9, etc., and restores granulocytic differentiation potential in C/EBPa p30-expressing AML cells [32].…”