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

SIMPLE SUMMARY: The protein methyltransferase SETD7 is essential for epigenetic regulation through methylation of histone H3 and non-histone proteins, including cell cycle, apoptosis and metastasis regulators. This multi-faceted role of SETD7 is cell context-and tissue type-dependent, which makes it difficult to interpret results in the framework of the current literature and to advance research in the field. The aim of this systematic review is to provide an updated description of how SETD7 impacts cancer-related processes considering different cancer types in different cell contexts. In the first part of this systematic review, we characterise the literature and in the second part, we provide a critical assessment of the findings from different cancer types. In the last part of this work, we integrate the findings and summarise the main signalling networks regulated by SETD7 to identify outcomes conserved across studies and propose ways to advance research related to SETD7. ABSTRACT: 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.