Chromatin associated SETD3 negatively regulates VEGF expression

Abstract

SETD3 is a member of the protein lysine methyltransferase (PKMT) family, which catalyzes the addition of methyl group to lysine residues. Accumulating data suggest that PKMTs are involved in the regulation of a broad spectrum of biological processes by targeting histone and non-histone proteins. Using a proteomic approach, we have identified 172 new SETD3 interacting proteins. We show that SETD3 binds and methylates the transcription factor FoxM1, which has been previously shown to be associated with the regulation of VEGF expression. We further demonstrate that under hypoxic conditions SETD3 is down-regulated. Mechanistically, we find that under basal conditions, SETD3 and FoxM1 are enriched on the VEGF promoter. Dissociation of both SETD3 and FoxM1 from the VEGF promoter under hypoxia correlates with elevated expression of VEGF. Taken together, our data reveal a new SETD3-dependent methylation-based signaling pathway at chromatin that regulates VEGF expression under normoxic and hypoxic conditions.

SETD3 acts as a prognostic marker in breast cancer patients and modulates the viability and invasion of breast cancer cells

“…7). Our study could, therefore, confirm the observation of Cohn et al that SETD3 regulates the expression of FoxM1 21 . Nevertheless, the discrepancy that we observed in our Kaplan-Meier analysis where the SETD3 expression correlates with a good prognosis while FOXM1 with a bad prognosis in patients with ER-positive tumors could be due to the following reasons: 1) the expression of FOXM1 (up-or down-regulation) is not only regulated by SETD3 but is also regulated by a wide range of factors such as c-Myc, H-Ras, N-Ras, EGFR (epidermal growth factor receptor), ErbB1, HER2/Neu (ErbB2), Notch1, STAT3 (signal transducer and activator of transcription 3), KLF4, GATA3, and others 59 .…”

“…According to our and other studies, it seems that SETD3 significantly regulates mechanisms associated with actin regulation, however, the protein network in which SETD3 is involved is unknown. Cohn et al demonstrated that SETD3 can interact with 172 novel proteins such as transcription factors of which FoxM1 was one of them 21 . Also, SETD3 methylates FoxM1 and negatively regulates the expression of Vascular Endothelial Growth Factor (VEGF) under normoxia conditions 21 , a known factor related to angiogenesis and tumor progression 58 .…”

“…In breast cancer, the forkhead box protein M1 (FoxM1) has tumor-promoting functions impacting patient prognosis 20 . FoxM1 is also methylated by SETD3, claiming a core position in oncogenesis 21 . It was demonstrated that SETD3 is a factor with relevance to cell cycle regulation.…”

“…Supporting findings suggest that SETD3 is required for p53 target recruitment and activation 23 . This identifies several relevant targets; the phenotypical and physical properties due to changes in beta-actin methylation (yet characterized by primary dystocia) and signaling properties of SETD3 that may affect oncogenesis 10,21 . Based on this evidence, we hypothesize that alterations in SETD3 expression may affect cytoskeletal function, cancer cell motility and clinical outcome in breast cancer patients.…”

Histone methylation and vascular biology

“…Furthermore, SET7 associates with GATA1 to promote VEGFA transcription and breast tumor angiogenesis [125]. However, by using ProtoArray system, Cohn et al identified 172 new SETD3 interacting proteins, and further investigation found that SETD3 binds and methylates the transcription factor FoxM1 to inhibit VEGFA expression under hypoxia [126]. In addition, GSK126, an EZH2 inhibitor, inhibits gastric cancer and lung adenocarcinoma cell migration and angiogenesis in solid tumor cell lines through downregulation of VEGFA expression [127].…”