SETDB1 accelerates tumourigenesis by regulating the WNT signalling pathway

Abstract

We investigated the oncogenic role of SETDB1 focusing on non-small cell lung cancer (NSCLC) having high expression of this protein. A total of 387 lung cancer cases were examined by immunohistochemistry, 72% of NSCLC samples were positive for SETDB1 staining, compared to 46% samples of normal bronchial epithelium (106 cases) (p<0.0001). Percent positive cells and intensity of staining increased significantly with increased grade of disease. Forced expression of SETDB1 in NSCLC cell lines enhanced their clonogenic growth in vitro and markedly increased tumor size in a murine xenograft model; while silencing (shRNA) SETDB1 in NSCLC cells slowed their proliferation. SETDB1 positively stimulated activity of the WNT/β-catenin pathway and diminished P53 expression resulting in enhanced NSCLC growth in vitro and in vivo. Our finding suggests therapeutic targeting SETDB1 may benefit patients whose tumors express high levels of SETDB1.

ATF7IP-Mediated Stabilization of the Histone Methyltransferase SETDB1 Is Essential for Heterochromatin Formation by the HUSH Complex

“…Alternatively, ATF7IP could simply act as a safety mechanism to prevent SETDB1 overactivity. Amplification of SETDB1 is heavily implicated in tumorigenesis (Ceol et al., 2011, Fei et al., 2015, Rodriguez-Paredes et al., 2014, Sun et al., 2014, Sun et al., 2015, Wong et al., 2016), and upregulation of ATF7IP has been observed in a number of tumors (Liu et al., 2009), suggesting that overexpression of SETDB1 could have deleterious effects. Given that no effective small molecule inhibitors of SETDB1 catalytic activity have been developed, our data raise the possibility that an alternative strategy to inhibit SETDB1 activity could be to target ATF7IP.…”

“…However, four additional methyltransferases (G9a, GLP, SUV39H1, and SUV39H2) are also known to target H3K9, raising the question as to how the activities of these enzymes are coordinately regulated to generate the required distribution of H3K9 methylation across the genome (Mozzetta et al., 2015). The importance of correct regulation of SETDB1 is underscored by the oncogenic potential of SETDB1 overexpression, with amplification of SETDB1 implicated in the progression of malignant melanoma (Ceol et al., 2011) and cancers of the prostate (Sun et al., 2014), liver (Fei et al., 2015, Wong et al., 2016), and lung (Rodriguez-Paredes et al., 2014, Sun et al., 2015). …”

Quantitative proteomic study of human prostate cancer cells with different metastatic potentials

“…A study has demonstrated the role of histone lysine methyltransferases SUV39H1 and SETDB1 in gliomagenesis and its association with cell proliferation, migration, and colony formation (43). Another study found that SETDB1 positively stimulated the WNT/β-catenin pathway and decreased P53 expression, resulting in enhanced non-small cell lung cancer growth in vitro and in vivo (44). Some authors have shown that miR-7, which is downregulated in the breast cancer MCF-7 and MDA-MB-231 cell lines, inhibited cell invasion and metastasis, decreased the breast cancer stem cell population, and partially reversed the epithelial-mesenchymal transition in MDA-MB-231 cells by directly targeting SETDB1 (45).…”

“…The data from the GeneCards database show that the SETDB1 protein is involved in three classical pathways: chromatin regulation/acetylation, non-canonical Wnt signaling, and lysine degradation. A number of studies suggest that SETDB1 promotes tumorigenesis and metastasis through the WNT/β-catenin pathway (44,47). However, further studies are required to assess this point.…”

Histone profiles in cancer

“…Amplifications of SETDB1 have been reported in 20% of lung adenocarcinoma and squamous cell carcinoma, and funcional studies suggest a contribution to tumorigenesis, possibly through modulatin of the wnt pathway (Rodriguez-Paredes et al, 2014;Wu et al, 2014;Sun et al, 2015). Furthermore, SETDB1 is likely the critical gene in the recurrent large amplification of chromosome 1q21 in melanoma (Ceol et al, 2011).…”