Small-Molecule Inhibitors of the Protein Methyltransferase SET7/9 Identified in a High-Throughput Screen

Francis, Nicola-Jane; Rowlands, Martin; Workman, Paul; Jones, Keith; Aherne, Wynne

doi:10.1177/1087057112452137

Cited by 14 publications

(13 citation statements)

References 17 publications

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“…Since both GATA1 and SET7 are overexpressed in breast cancer patients, and GATA1 and SET7 promote not only breast cancer cell growth but also tumor angiogenesis, inhibition of GATA1 and/or SET7 may be a useful strategy for breast cancer therapy. Recently, SET7 inhibitors have been identified [ 48 ]. It will be interesting to investigate whether these inhibitors repress cancer cell growth and tumor angiogenesis.…”

Section: Discussionmentioning

confidence: 99%

The transcription factor GATA1 and the histone methyltransferase SET7 interact to promote VEGF-mediated angiogenesis and tumor growth and predict clinical outcome of breast cancer

et al. 2016

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Angiogenesis is essential for tumor growth. Vascular endothelial growth factor (VEGF) is the most important regulator of tumor angiogenesis. However, how transcription factors interact with histone-modifying enzymes to regulate VEGF transcription and tumor angiogenesis remains unclear. Here, we show that transcription factor GATA1 associates with the histone methyltransferase SET7 to promote VEGF transcription and breast tumor angiogenesis. Using chromatin immunoprecipitation assay, we found that GATA1 was required for recruitment of SET7, RNA polymerase II and transcription factor II B to VEGF core promoter. GATA1 enhanced breast cancer cell (MCF7, ZR75-1 and MDA-MB-231)-secreted VEGF via SET7, which promoted vascular endothelial cell (HUVEC) proliferation, migration and tube formation. SET7 was required for GATA1-induced breast tumor angiogenesis and growth in nude mice. Immunohistochemical staining showed that expression of GATA1 and SET7 was upregulated and positively correlated with VEGF expression and microvessel number in 80 breast cancer patients. GATA1 and SET7 are independent poor prognostic factors in breast cancer. Our data provide novel insights into VEGF transcriptional regulation and suggest GATA1/SET7 as cancer therapeutic targets.

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Section: Discussionmentioning

confidence: 99%

The transcription factor GATA1 and the histone methyltransferase SET7 interact to promote VEGF-mediated angiogenesis and tumor growth and predict clinical outcome of breast cancer

et al. 2016

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“…Future xenograft assays are planned to further confirm our findings. Recently, several SET9 inhibitors with high potency and selectivity have been developed in high throughput screening assays [48]. However, the role of SET9 in disease pathways was poorly understood.…”

Section: Discussionmentioning

confidence: 99%

Functional regulation of hypoxia inducible factor-1α by SET9 lysine methyltransferase

Liu

Geng

Xue

et al. 2015

Biochimica et Biophysica Acta (BBA) - Molecular Cell Research

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HIF-1α is degraded by oxygen-dependent mechanisms but stabilized in hypoxia to form transcriptional complex HIF-1, which transactivates genes promoting cancer hallmarks. However, how HIF-1α is specifically regulated in hypoxia is poorly understood. Here, we report that the histone methyltransferase SET9 promotes HIF-1α protein stability in hypoxia and enhances HIF-1 mediated glycolytic gene transcription, thereby playing an important role in mediating cancer cell adaptation and survival to hypoxic stress. Specifically, SET9 interacts with HIF-1α and promotes HIF-1α protein stability in hypoxia. Silencing SET9 by siRNA reduces HIF-1α protein stability in hypoxia, and attenuates the hypoxic induction of HIF-1 target genes mediating hypoxic glycolysis. Mechanistically, we find that SET9 is enriched at the hypoxia response elements (HRE) within promoters of the HIF-1-responsive glycolytic genes. Silencing SET9 reduces HIF-1α levels at these HREs in hypoxia, thereby attenuating HIF-1-mediated gene transcription. Further, silencing SET9 by siRNA reduces hypoxia-induced glycolysis and inhibits cell viability of hypoxic cancer cells. Our findings suggest that SET9 enriches at HRE sites of HIF-1 responsive glycolytic genes and stabilizes HIF-1α at these sites in hypoxia, thus establishes an epigenetic mechanism of the metabolic adaptation in hypoxic cancer cells.

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“…This clearly illustrates the context specificity of the SETD7 function. Moreover, there are several SETD7 inhibitors currently available [17][18][19][20][21][22][23] and some studies have suggested SETD7 inhibition as a potential anti-cancer therapy [20][21][22]. Therefore, there is a need to systematise current findings to identify the contexts that can lead to improvements in cancer diagnosis and therapy.…”

Section: Introductionmentioning

confidence: 99%

A Systematic Review to Define the Multi-Faceted Role of Lysine Methyltransferase SETD7 in Cancer

Monteiro

Williams

Helguero

2022

Cancers

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Histone–lysine N-methyltransferase SETD7 regulates a variety of cancer-related processes, in a tissue-type and signalling context-dependent manner. To date, there is no consensus regarding SETD7´s biological functions, or potential for cancer diagnostics and therapeutics. In this work, we summarised the literature on SETD7 expression and function in cancer, to identify the contexts where SETD7 expression and targeting can lead to improvements in cancer diagnosis and therapy. The most studied cancers were found to be lung and osteosarcoma followed by colorectal and breast cancers. SETD7 mRNA and/or protein expression in human cancer tissue was evaluated using public databases and/or in-house cohorts, but its prognostic significance remains inconclusive. The most studied cancer-related processes regulated by SETD7 were cell proliferation, apoptosis, epithelial-mesenchymal transition, migration and invasion with special relevance to the pRb/E2F-1 pathway. SETD7 consistently prevented epithelial to mesenchymal transition in different cancer types, and inhibition of its function appears to be associated with improved response to DNA-damaging agents in most of the analysed studies. Stabilising mutations in SETD7 target proteins prevent their methylation or promote other competing post-translational modifications that can override the SETD7 effect. This indicates that a clear discrimination of these mutations and competing signalling pathways must be considered in future functional studies.

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Small-Molecule Inhibitors of the Protein Methyltransferase SET7/9 Identified in a High-Throughput Screen

Cited by 14 publications

References 17 publications

The transcription factor GATA1 and the histone methyltransferase SET7 interact to promote VEGF-mediated angiogenesis and tumor growth and predict clinical outcome of breast cancer

The transcription factor GATA1 and the histone methyltransferase SET7 interact to promote VEGF-mediated angiogenesis and tumor growth and predict clinical outcome of breast cancer

Functional regulation of hypoxia inducible factor-1α by SET9 lysine methyltransferase

A Systematic Review to Define the Multi-Faceted Role of Lysine Methyltransferase SETD7 in Cancer

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