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

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.

SETD7 Expression Is Associated with Breast Cancer Survival Outcomes for Specific Molecular Subtypes: A Systematic Analysis of Publicly Available Datasets

“…SETD7 impacts cancer-related processes, including in BC [ 4 , 49 ], but it was not mutated in BC (as shown above). Therefore, mutations in SETD7 target genes were queried.…”

“…SETD7 may also be important to prevent oxidative stress in BC cells by reducing KEAP1 and enhancing the expression of GSTT2 and NFE2L2 (Nrf2), and promote metastasis by enhancing VEGFA or RUNX2 expression [ 3 ]. On the other hand, SETD7 can methylate oncogenic proteins (DNMT1, E2F1, and HIF1A), leading to their degradation (reviewed in [ 4 ]). Data obtained mainly from preclinical models point toward a context-dependent effect mediated by SETD7, and its role in BC remains controversial [ 4 ].…”

“…On the other hand, SETD7 can methylate oncogenic proteins (DNMT1, E2F1, and HIF1A), leading to their degradation (reviewed in [ 4 ]). Data obtained mainly from preclinical models point toward a context-dependent effect mediated by SETD7, and its role in BC remains controversial [ 4 ].…”

“…In a recent systematic review, we were able to associate high SETD7 activity with inhibition of epithelial–mesenchymal transition in all the cancer types where this process had been studied, including BC [ 4 ]. Moreover, inhibition of SETD7 function was associated with improved response to DNA-damaging agents in most of the analysed studies [ 4 ].…”

“…In a recent systematic review, we were able to associate high SETD7 activity with inhibition of epithelial–mesenchymal transition in all the cancer types where this process had been studied, including BC [ 4 ]. Moreover, inhibition of SETD7 function was associated with improved response to DNA-damaging agents in most of the analysed studies [ 4 ]. Thus, while effects mediated by SETD7 are cell type- and signalling context-specific, the lack of clarity regarding the role and clinical significance of SETD7 in BC may lead to stagnation in this field of research before clear conclusions can be drawn.…”