Abstract
SETD7 is a methyltransferase that specifically catalyzes the monomethylation of lysine 4 on histone H3. A variety of studies has revealed the role of SETD7 in posttranslational modifications of non-histone proteins. However, the prognostic value of SETD7 on breast cancer and the ability of SETD7 of regulating intrinsic redox homeostasis has never been investigated. In this study, using The Cancer Genome Atlas (TCGA) database, we revealed that SETD7 was a potential prognostic marker of breast cancer. Median survival time of patients with low SETD7 expression (18.1 years) was twice than that of SETD7 low-expressed patients (9.5 years). We demonstrated that SETD7 promoted tumor cell proliferation and prevented cell apoptosis and that SETD7 delicately maintained the redox homeostasis through regulating the levels of GSH/GSSG and ROS. Further studies indicated that SETD7 was a positive activator of KEAP1-NRF2 pathway. Using dual luciferase assay, we revealed the role of SETD7 as a transcriptional activator of antioxidant enzymes. Downregulation of SETD7 in MCF7 and MDA-MB-231 cells impaired the expression of antioxidant enzymes and induces imbalance of redox status. Together, we proposed SETD7 as a prognostic marker of breast cancer and a novel antioxidant promoter under oxidative stress in breast cancer.
Highlights
IntroductionSETD7 ( known as SET7, SET9 and SET7/9), a SET domain containing lysine methyltransferase 7, monomethylates lysine 4 at histone 3 (H3K4me1) and activates its involved genes expression [1]
SETD7, a SET domain containing lysine methyltransferase 7, monomethylates lysine 4 at histone 3 (H3K4me1) and activates its involved genes expression [1]
We demonstrated that SETD7 promoted tumor cell proliferation and prevented cell apoptosis and that SETD7 delicately maintained the redox homeostasis through regulating the levels of GSH/GSSG and reactive oxygen species (ROS)
Summary
SETD7 ( known as SET7, SET9 and SET7/9), a SET domain containing lysine methyltransferase 7, monomethylates lysine 4 at histone 3 (H3K4me1) and activates its involved genes expression [1]. SETD7 has been discovered to monomethylate a series of non-histone proteins, such as p53 [2], DNA cytosine methyltransferase 1 (DNMT1) [3], E2 promoter-binding factor 1 (E2F1) [4, 5], hypoxiainducible factor 1α (HIF1α) [6, 7], YAP [8] and NF-κb [9]. These methylations lead to various and even contradictory results. Most studies hold the opinion that high ROS levels are detrimental to cancer cells, because excessive ROS can induce DNA damage and apoptosis [13,14,15,16]
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