WDR5-Myc axis promotes the progression of glioblastoma and neuroblastoma by transcriptional activating CARM1

Wang, Feng; Zhang, Jiayi; Ke, Xiaoxue; Peng, Wen; Zhao, Gaichao; Peng, Shihan; Xu, Jie; Xu, Bo; Cui, Hongjuan

doi:10.1016/j.bbrc.2019.12.101

Cited by 18 publications

(11 citation statements)

References 35 publications

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“…Moreover, it has only recently been identified that the Win binding site is implicated in transient protein-protein interactions with dozens of proteins, including those involved in PI3K signaling [36]. Given that WDR5 is overexpressed under various oncogenic conditions [47][48][49], the Win binding site has become a key therapeutic target for different cancers [24,25,[50][51][52][53][54][55][56][57][58][59]. Therefore, a better mechanistic and quantitative understanding of the interactions of the Win binding site with other Win motif partners has fundamental and clinical significance [60][61][62][63][64].…”

Section: Introductionmentioning

confidence: 99%

Kinetics of the multitasking high-affinity Win binding site of WDR5 in restricted and unrestricted conditions

Imran

Moyer²,

Canning

et al. 2021

Biochemical Journal

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Recent advances in quantitative proteomics show that WD40 proteins play a pivotal role in numerous cellular networks. Yet, they have been fairly unexplored and their physical associations with other proteins are ambiguous. A quantitative understanding of these interactions has wide-ranging significance. WD40 repeat protein 5 (WDR5) interacts with all members of human SET1/MLL methyltransferases, which regulate methylation of the histone 3 lysine 4 (H3K4). Here, using real-time binding measurements in a high-throughput setting, we identified the kinetic fingerprint of transient associations between WDR5 and 14-residue WDR5 interaction (Win) motif peptides of each SET1 protein (SET1Win). Our results reveal that the high-affinity WDR5-SET1Win interactions feature slow association kinetics. This finding is likely due to the requirement of SET1Win to insert into the narrow WDR5 cavity, also named the Win binding site. Furthermore, our explorations indicate fairly slow dissociation kinetics. This conclusion is in accordance with the primary role of WDR5 in maintaining the functional integrity of a large multisubunit complex, which regulates the histone methylation. Because the Win binding site is considered a key therapeutic target, the immediate outcomes of this study could form the basis for accelerated developments in medical biotechnology.

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Section: Introductionmentioning

confidence: 99%

Kinetics of the multitasking high-affinity Win binding site of WDR5 in restricted and unrestricted conditions

Imran

Moyer²,

Canning

et al. 2021

Biochemical Journal

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“…Knockdown induced by shRNAs against CARM1 mRNA in glioblastoma (LN229) and neuroblastoma [BE(2)-C] cell lines inhibited the proliferation in both cell types, demonstrating the functional impact of this gene in both brain tumors. 53 These authors also found that CARM1 downregulation was associated with decreasing mRNA or protein levels of LDHA, GLUT1, and ASCT2 genes. The results of Wang et al suggest that CARM1 may be involved in the regulation of glycolysis and glutaminolysis in glioblastoma and neuroblastoma.…”

Section: Discussionmentioning

confidence: 91%

Expression of pluripotency-related genes in human glioblastoma

Rios

Tirapelli

Cirino

et al. 2021

Neuro-Oncology Advances

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Background Cancer is a group of heterogeneous diseases characterized by several disruptions of the genetic and epigenetic components of cell biology. Some types of cancer have been shown to be constituted by a mosaic of cells with variable differentiation states, with more aggressive tumors being more undifferentiated. In most cases, undifferentiated tumor cells express associated embryonic markers such as the OCT4, NANOG, SOX2 and CARM1 genes. The ectopic or reminiscent expression of some master regulator genes of pluripotency has been indicated as the cause of the poorly differentiated state of tumors, and based on the evidence of some reports, can be used as a possible therapeutic target. Considering this information, a more detailed investigation of the expression of pluripotency-associated genes is necessary to evaluate the roles of these genes in the etiology of some tumors and their use targets of therapy. Methods The expression of four pluripotency-related genes was investigated (OCT4, NANOG, SOX2 and CARM1) in the most malignant primary human brain tumor, glioblastoma (GBM). Results and Conclusion The results demonstrated a signature of OCT4/SOX2/CARM1 genes and a significant increase of CARM1 expression in GBM cases.

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“…However while WDR5 appears to be expressed in GBM and neuroblastoma and functionally important in high-passage GBM models (Wang et al, 2020), WDR5 has not been extensively investigated in GBM CSCs or in the context of anti-GBM therapy.…”

Section: Resultsmentioning

confidence: 99%

WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma

Mitchell

Shakya

Silver

et al. 2021

Preprint

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Glioblastomas (GBMs) are heterogeneous, treatment-resistant tumors that are driven by populations of cancer stem cells (CSCs). Despite their importance for tumor growth, few molecular mechanisms critical for CSC population maintenance have been exploited for therapeutic development. We employed spatially resolved loss-of-function screening in GBM patient-derived organoids to identify essential epigenetic regulators and identified WDR5 as indispensable for CSCs. WDR5 is a component of the WRAD complex, which promotes SET1-family-mediated Lys4 methylation of histone H3, associated with positive regulation of transcription. Genetic and pharmacologic inhibition of WDR5 reduced growth and self-renewal of CSCs as well as CSC-mediated tumor growth. Further, WDR5 inhibitors partially blocked WRAD complex assembly, reduced H3K4 trimethylation, and inhibited tumor growth. These findings highlight the role of WDR5 and the WRAD complex in CSCs for maintaining the CSC state and provide a rationale for therapeutic development of WRAD complex inhibitors for GBM and other advanced cancers.

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WDR5-Myc axis promotes the progression of glioblastoma and neuroblastoma by transcriptional activating CARM1

Cited by 18 publications

References 35 publications

Kinetics of the multitasking high-affinity Win binding site of WDR5 in restricted and unrestricted conditions

Kinetics of the multitasking high-affinity Win binding site of WDR5 in restricted and unrestricted conditions

Expression of pluripotency-related genes in human glioblastoma

WDR5 represents a therapeutically exploitable target for cancer stem cells in glioblastoma

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