Upregulated WDR5 promotes proliferation, self-renewal and chemoresistance in bladder cancer via mediating H3K4 trimethylation

Chen, Zhanghua; Xie, Weibin; Gu, Peng; Cai, Qingqing; Wang, Bo; Xie, Yun; Dong, Wen; Wang, He; Zhong, Guangzheng; Lin, Tianxin; Huang, Jian

doi:10.1038/srep08293

Cited by 112 publications

(126 citation statements)

References 48 publications

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“…Recently, WDR5 upregulation was detected in prostate and bladder cancers, where it was also found to be critical for cancer cell proliferation (Kim et al, 2014;Chen et al, 2015). We first confirmed deregulated expression of WDR5 in human PDAC compared to normal control pancreas ( Figure 3A).…”

Section: Wdr5 Is Essential For Pdac Initiation and Proliferationsupporting

confidence: 78%

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

et al. 2016

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Current treatment regimens for pancreatic ductal adenocarcinoma (PDAC) yield poor 5-year survival, emphasizing the critical need to identify druggable targets essential for PDAC maintenance. We developed an unbiased and in vivo target discovery approach to identify molecular vulnerabilities in low-passage and patient-derived PDAC xenografts or genetically engineered mouse model-derived allografts. Focusing on epigenetic regulators, we identified WDR5, a core member of the COMPASS histone H3 Lys4 (H3K4) MLL (1-4) methyltransferase complex, as a top tumor maintenance hit required across multiple human and mouse tumors. Mechanistically, WDR5 functions to sustain proper execution of DNA replication in PDAC cells, as previously suggested by replication stress studies involving MLL1, and c-Myc, also found to interact with WDR5. We indeed demonstrate that interaction with c-Myc is critical for this function. By showing that ATR inhibition mimicked the effects of WDR5 suppression, these data provide rationale to test ATR and WDR5 inhibitors for activity in this disease.

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Section: Wdr5 Is Essential For Pdac Initiation and Proliferationsupporting

confidence: 78%

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

et al. 2016

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“…WDR5, a core component of the histone H3K4 methyltransferase complex, is crucial for vertebrate development and plays an important role in the self-renewal of pluripotent cells and cell differentiation (39,55). Multiple studies have recently documented that dysregulated WDR5 is involved in promoting cancer metastasis and chemoresistance (56,57), suggesting that WDR5 may serve as a therapeutic target for cancer (58). However, WDR5 is extensively expressed in numerous cell types and plays important roles in various biological functions (39,55,59,60).…”

Section: Blockage Of Vegf-c Reverses Blacat2-induced Ln Metastasis Inmentioning

confidence: 99%

Long noncoding RNA BLACAT2 promotes bladder cancer–associated lymphangiogenesis and lymphatic metastasis

Wang¹,

Zhong²,

Jiang³

et al. 2018

Journal of Clinical Investigation

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“…[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]. However, it has no report about the WDR5 global binding gene targets in leukemia cells.…”

Section: Discussionmentioning

confidence: 99%

“…WDR5 is hyperexpressed and critical for cell proliferation and H3K4 methylation in human neuroblastoma, prostate cancers and bladder cancers [33–36]. However, very little is known about the role of WDR5 in leukemia, despite our growing knowledge about MLL1 fusion proteins and leukemia.…”

Section: Introductionmentioning

confidence: 99%

WDR5 high expression and its effect on tumorigenesis in leukemia

Song

Kawasawa

et al. 2016

Oncotarget

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WD repeat domain 5 (WDR5) plays an important role in various biological functions through the epigenetic regulation of gene transcription. However, the oncogenic effect of WDR5 in leukemia remains largely unknown. Here, we found WDR5 expression is increased in leukemia patients. High expression of WDR5 is associated with high risk leukemia; Patients with WDR5 and MLL1 high expression have poor complete remission rate. We further identified the global genomic binding of WDR5 in leukemic cells and found the genomic co-localization of WDR5 binding with H3K4me3 enrichment. Moreover, WDR5 knockdown by shRNA suppresses cell proliferation, induces apoptosis, inhibits the expression of WDR5 targets, and blocks the H3K4me3 enrichment on the promoter of its targets. We also observed the positive correlation of WDR5 expression with these targets in the cohort study of leukemia patients. Our data reveal that WDR5 may have oncogenic effect and WDR5-mediated H3K4 methylation plays an important role in leukemogenesis.

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Upregulated WDR5 promotes proliferation, self-renewal and chemoresistance in bladder cancer via mediating H3K4 trimethylation

Cited by 112 publications

References 48 publications

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

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

Long noncoding RNA BLACAT2 promotes bladder cancer–associated lymphangiogenesis and lymphatic metastasis

WDR5 high expression and its effect on tumorigenesis in leukemia

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