WDR5 supports colon cancer cells by promoting methylation of H3K4 and suppressing DNA damage

Neilsen, Beth K.; Chakraborty, Binita; McCall, Jamie L.; Frodyma, Danielle E.; Sleightholm, Richard; Fisher, Kurt W.; Lewis, Robert E.

doi:10.1186/s12885-018-4580-6

Cited by 37 publications

(35 citation statements)

References 60 publications

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“…Early formation of neuroblastoma. In breast cancer, WDR5 has been reported to promote breast cancer proliferation through CBX8 interaction activation of the Notch pathway (Neilsen et al, 2018). WDR5 expression levels are associated with poor prognosis in breast cancer patients (Dai et al, 2015).…”

Section: Discussionmentioning

confidence: 99%

VASP is upregulated by WDR5-MYC nexus and promotes cell migration in breast cancer

Tian

Chen

et al. 2020

Preprint

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Abstract Backguroud: Breast cancer is one of the most threatening diseases for women, whose metastasis and recurrence are important causes of death in breast cancer patients. Vasodilator-stimulated phosphoprotein (VASP) is a cytoskeletal regulatory protein that promotes invasion and metastasis of tumor cells by regulating cell migration. Bioinformatics data indicated that H3K4me3, WDR5 and MYC co-enriched in the VASP promoter region. Aims: The purpose of this study is to demonstrate the regulatory function and mechanism of WDR5-MYC nexus complex on VASP in breast cancer.Method: In this present study, the expression of VASP in breast cancer and adjacent normal tissues was detected by RT-qPCR. The enrichment of H3K4me3, WDR5 and MYC on the VASP promoter was analyzed by ChIPseeker R package and verified by ChIP-PCR. The interaction of H3K4me3, WDR5 and MYC in breast cancer cells was detected by immunoprecipitation and immunofluorescence. Transcriptional activation function of MYC on VASP was detected by site-directed mutagenesis and dual fluorescence reporter system. The regulatory effect of WDR5 on breast cancer cell migration was tested by wund healing and transwell.Result: VASP is up-regulated in breast cancer tissues as compared with adjacent normal tissues. There is interaction between H3K4me3, WDR5 and MYC and co-enrichment on the VASP promoter. MYC can activate VASP transcription by binding to the VASP promoter-842 binding site. WDR5 and MYC can enhance the migration ability of breast cancer cells by up-regulating VASPConclusion: Our results suggest that WDR5-MYC nexus can activate the transcription of VASP by binding to the VASP promoter region, and promote the migration of breast cancer by up-regulating the expression level of VASP.

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Section: Discussionmentioning

confidence: 99%

VASP is upregulated by WDR5-MYC nexus and promotes cell migration in breast cancer

Tian

Chen

et al. 2020

Preprint

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“…However, both WDR5 and DPY30 depletion display an opposite phenotype as the one observed upon ASH2L knockdown. Down-regulation of WDR5 in colorectal cancer induces DNA damage and chemosensitivity (55), and knockdown of DPY30 increases the levels of endogenous DNA damage and decrease the DNA repair ability of hematopoietic stem cells (56). What seems to stand out about ASH2L is that it is the only core member of the methyl-transferase complexes that is required for the addition of the third methyl group.…”

Section: Discussionmentioning

confidence: 99%

ASH2L drives proliferation and sensitivity to bleomycin and other genotoxins in Hodgkin’s lymphoma and testicular cancer cells

Constantin

Widmann

2020

Preprint

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It is of clinical importance to identify biomarkers predicting the efficacy of DNA damaging drugs (genotoxins) so that non-responders are not unduly exposed to the deleterious effects of otherwise inefficient drugs. Using a whole genome CRISPR/Cas9 gene knockout approach we have identified that low levels of ASH2L cause resistance to genotoxins. ASH2L is a core component of the H3K4 methyl transferase complex. We show that ASH2L absence decreases cell proliferation and favors DNA repair upon genotoxin exposure. The cell models we have used are derived from cancers currently treated either partially (Hodgkin’s lymphoma), or entirely (testicular cancer) with genotoxins. For such cancers, ASH2L levels could be used as a biomarker to predict the response to genotoxins. Our data also indicate that patients with low ASH2L expressing tumors do not develop resistance to ATR inhibitors. In these patients, such inhibitors may represent an alternative treatment to DNA damaging drugs.

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“…Recent studies have revealed that WDR5 plays key roles in the tumorigenesis and progression of a variety of cancers ( 34 , 35 , 44 , 55 – 60 ). Myc family oncoproteins are among the most prevalent oncogenic transcription factors, and c-Myc and N-Myc induce tumorigenesis by regulating gene transcription in human cancer tissues of various organ origins ( 34 , 35 , 55 ).…”

Section: The Role Of Wdr5 In Cancermentioning

confidence: 99%

“…WDR5 is over-expressed in gastric and colon cancer cell lines and human tumor tissues, and high levels of WDR5 expression in tumor tissues is associated with poor patient survival rate ( 59 , 60 ). Mechanistically, in gastric cancer cells, WDR5 induces histone H3K4 trimethylation at the Cyclin D1 gene promoter and Cyclin D1 gene transcription, leading to cancer cell proliferation ( 59 ).…”

Section: The Role Of Wdr5 In Cancermentioning

confidence: 99%

“…Mechanistically, in gastric cancer cells, WDR5 induces histone H3K4 trimethylation at the Cyclin D1 gene promoter and Cyclin D1 gene transcription, leading to cancer cell proliferation ( 59 ). In colon cancer cells, WDR5 decreases the phosphorylation of the histone protein H2AX and induces H3K4 trimethylation, leading to colon cancer cell proliferation and survival, and WDR5 depletion sensitizes colon cancer cells to radiation-induced DNA damage ( 60 ).…”

Section: The Role Of Wdr5 In Cancermentioning

confidence: 99%

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The Histone H3 Lysine 4 Presenter WDR5 as an Oncogenic Protein and Novel Epigenetic Target in Cancer

He²,

et al. 2018

Front. Oncol.

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The histone H3 lysine 4 (H3K4) presenter WDR5 forms protein complexes with H3K4 methyltransferases MLL1-MLL4 and binding partner proteins including RBBP5, ASH2L, and DPY30, and plays a key role in histone H3K4 trimethylation, chromatin remodeling, transcriptional activation of target genes, normal biology, and diseases such as MLL-rearranged leukemia. By forming protein complexes with other proteins such as Myc, WDR5 induces transcriptional activation of key oncogenes, tumor cell cycle progression, DNA replication, cell proliferation, survival, tumor initiation, progression, invasion, and metastasis of cancer of a variety of organ origins. Several small molecule MLL/WDR5 protein-protein interaction inhibitors, such as MM-401, MM-589, WDR5-0103, Piribedil, and OICR-9429, have been confirmed to reduce H3K4 trimethylation, oncogenic gene expression, cell cycle progression, cancer cell proliferation, survival and resistance to chemotherapy without general toxicity to normal cells. Derivatives of the MLL/WDR5 interaction inhibitors with improved pharmacokinetic properties and in vivo bioavailability are expected to have the potential to be trialed in cancer patients.

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WDR5 supports colon cancer cells by promoting methylation of H3K4 and suppressing DNA damage

Cited by 37 publications

References 60 publications

VASP is upregulated by WDR5-MYC nexus and promotes cell migration in breast cancer

VASP is upregulated by WDR5-MYC nexus and promotes cell migration in breast cancer

ASH2L drives proliferation and sensitivity to bleomycin and other genotoxins in Hodgkin’s lymphoma and testicular cancer cells

The Histone H3 Lysine 4 Presenter WDR5 as an Oncogenic Protein and Novel Epigenetic Target in Cancer

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