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Biological processes and signal transduction pathways regulated by the protein methyltransferase SETD7 and their significance in cancer.

ABSTRACT: Protein methyltransferases have been shown to methylate histone and non-histone proteins, leading to regulation of several biological processes that control cell homeostasis. Over the past few years, the histone-lysine N-methyltransferase SETD7 (SETD7; also known as SET7/9, KIAA1717, KMT7, SET7, SET9) has emerged as an important regulator of at least 30 non-histone proteins and a potential target for the treatment of several human diseases. This review discusses current knowledge of the structure and subcellular localization of SETD7, as well as its function as a histone and non-histone methyltransferase. This work also underlines the putative contribution of SETD7 to the regulation of gene expression, control of cell proliferation, differentiation and endoplasmic reticulum stress, which indicate that SETD7 is a candidate for novel targeted therapies with the aim of either stimulating or inhibiting its activity, depending on the cell signaling context.

SUBMITTER: Batista IAA

PROVIDER: S-EPMC6043541 | biostudies-other | 2018

REPOSITORIES: biostudies-other

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Biological processes and signal transduction pathways regulated by the protein methyltransferase SETD7 and their significance in cancer.

Batista Inês de Albuquerque Almeida IAA Helguero Luisa Alejandra LA

Signal transduction and targeted therapy 20180713

Protein methyltransferases have been shown to methylate histone and non-histone proteins, leading to regulation of several biological processes that control cell homeostasis. Over the past few years, the histone-lysine <i>N</i>-methyltransferase SETD7 (SETD7; also known as SET7/9, KIAA1717, KMT7, SET7, SET9) has emerged as an important regulator of at least 30 non-histone proteins and a potential target for the treatment of several human diseases. This review discusses current knowledge of the s ...[more]

PMID: 30013796

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Project description:Arachidonic acid (AA) is a polyunsaturated fatty acid present at high concentrations in the ovarian cancer (OC) microenvironment and associated with a poor clinical outcome. In the present study, we have unraveled a potential link between AA and macrophage functions. Methods: AA-triggered signal transduction was studied in primary monocyte-derived macrophages (MDMs) by phosphoproteomics, transcriptional profiling, measurement of intracellular Ca2+ accumulation and reactive oxygen species production in conjunction with bioinformatic analyses. Functional effects were investigated by actin filament staining, quantification of macropinocytosis and analysis of extracellular vesicle release. Results: We identified the ASK1 - p38δ/α (MAPK13/14) axis as a central constituent of signal transduction pathways triggered by non-metabolized AA. This pathway was induced by the Ca2+-triggered activation of calmodulin kinase II, and to a minor extent by ROS generation in a subset of donors. Activated p38 in turn was linked to a transcriptional stress response associated with a poor relapse-free survival. Consistent with the phosphorylation of the p38 substrate HSP27 and the (de)phosphorylation of multiple regulators of Rho family GTPases, AA impaired actin filament organization and inhibited actin-driven macropinocytosis. AA also affected the phosphorylation of proteins regulating vesicle biogenesis, and consistently, AA enhanced the release of tetraspanin-containing exosome-like vesicles. Finally, we identified phospholipase A2 group 2A (PLA2G2A) as the clinically most relevant enzyme producing extracellular AA, providing further potentially theranostic options. Conclusion: Our results suggest that AA contributes to an unfavorable clinical outcome of OC by impacting the phenotype of tumor-associated macrophages. Besides critical AA-regulated signal transduction proteins identified in the present study, PLA2G2A might represent a potential prognostic tool and therapeutic target to interfere with OC progression.

Project description:Arachidonic acid (AA) is a polyunsaturated fatty acid present at high concentrations in the ovarian cancer (OC) microenvironment and is associated with poor clinical outcome. In the present study, we elucidate a potential link between AA and pro-tumorigenic macrophage polarization. Methods: AA-triggered signal transduction was studied in primary monocyte-derived macrophages (MDMs) by phosphoproteomics, transcriptional profiling, measurement of intracellular Ca2+ accumulation and reactive oxygen species production in conjunction with bioinformatic analyses. Functional effects were investigated by actin filament staining, quantification of macropinocytosis and analysis of extracellular vesicle release. Results: We identified the ASK1 - p38 (MAPK13/14) axis as a central constituent of signal transduction pathways triggered by non-metabolized AA. This pathway was induced by the Ca2+-triggered activation of calmodulin kinase II, and to a minor extent by ROS generation in a subset of donors. Activated p38 in turn was linked to a transcriptional stress response associated with a poor relapse-free survival. Consistent with the phosphorylation of the p38 substrate HSP27 and the (de)phosphorylation of multiple regulators of Rho family GTPases, AA impaired actin filament organization and inhibited actin-driven macropinocytosis. AA also affected the phosphorylation of proteins regulating vesicle biogenesis, and consistently, AA enhanced the release of tetraspanin-containing exosomes. Finally, we identified phospholipase A2 Group 2A (PLA2G2A) as the clinically most relevant enzyme producing extracellular AA, providing further potentially theranostic options. Conclusion: Our results suggest that AA contributes to an unfavorable clinical outcome of OC by promoting the pro-tumorigenic phenotype of tumor-associated macrophages. Besides critical AA-regulated signal transduction proteins identified in the present study, PLA2G2A might represent a potential prognostic tool and therapeutic target to interfere with OC progression.

Dataset Information

Biological processes and signal transduction pathways regulated by the protein methyltransferase SETD7 and their significance in cancer.

Publications

Biological processes and signal transduction pathways regulated by the protein methyltransferase SETD7 and their significance in cancer.

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