Role of Histone Lysine Methyltransferases SUV39H1 and SETDB1 in Gliomagenesis: Modulation of Cell Proliferation, Migration, and Colony Formation

Abstract

Posttranslational modifications of histones are considered as critical regulators of gene expression, playing significant role in the pathogenesis and progression of tumors. Trimethylation of histone 3 lysine 9 (H3K9me3), a repressed transcription mark, is mainly regulated by the histone lysine N-methyltransferases (HKMTs), SUV39H1 and SETDB1. The present study investigated the implication of these HKMTs in glioma progression. SUV39H1 and SETDB1 expression was upregulated in glioma cell lines (GOS-3, 1321N1, T98G, U87MG) and in glioma tissues compared to normal brain being positively correlated with grade and histological malignancy. Suppression by siRNA of the two HKMTs for 24 and 48 h resulted in significantly reduced proliferation of GOS-3 and T98G glioma cells with siSUV39H1 effects been most prominent. Furthermore, HKMTs knockdown-induced apoptosis with a high rate of apoptotic cells have been observed after siSUV39H1 and siSETDB1 for both cell lines. Additionally, suppression of the two HKMTs reduced cell migration and clonogenic ability of both glioma cell lines. Our results indicate overexpression of SETDB1 and SUV39H1 in gliomas. Treatments that alter HKMT expression affect the proliferative and apoptotic rates in glioma cells as well as their migratory and colony formation capacity. These data suggest that both HKMTs and especially SUV39H1 may serve as novel biomarkers for future therapeutic targeting of these tumors.

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

“…SETDB1 has been established as an oncogene in a number of human carcinomas. 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).…”

Deregulation of Histone-Modifying Enzymes and Chromatin Structure Modifiers Contributes to Glioma Development

“…15 glioma cell lines and in glioma tissues compared with normal brains which correlated with histological malignancy. Treatments that altered SUV39H1 and SETDB1 expression affected proliferative and apoptotic potential as well as migratory and colony formation capacity of glioma cells [39].…”

“…H3S10ph AURKB Increased activity [27] H3K27me2,3 EZH2 Overexpression [33][34][35][36][37][38] H3Y41ph JAK2 Increased activity [27] H3K9me3 KMT1E (SETDB1) Overexpression [39] H3K36me3 KMT3A (SETD2) Mutation [40] H3K4me1 KMT7 (SETD7) Mutation [28] H3T6ph PKCβ Increased activity [27] H3T11ph PKM2 Overexpression [41] H4R3me2 PRMT1 Overexpression [42] H3K9me3 SUV39H Overexpression [39] Erasers Pan-histone acetylation HDAC2 Mutation [28] Pan-histone acetylation HDAC4 Downregulation [32] Pan-histone acetylation HDAC5 Downregulation [32] Pan-histone acetylation HDAC6 Downregulation [32] Pan-histone acetylation HDAC7 Downregulation [32] Pan-histone acetylation HDAC9 Downregulation Mutation [32] [ 28] pan-histone acetylation HDAC11 Downregulation [32] H3K4me1,2; H3K9me1,2 KDM1 (LSD1) Overexpression [43] H3K9me1,2 KDM3A (JMJD1A) Mutation [28] H3K9me1,2 KDM3B (JMJD1B) Mutation [28] H3K4me1,2,3 KDM5B (JARID1B) Overexpression [44] H3K27me3 KDM6B (JMJD3) Overexpression [45] Readers…”

Histone profiles in cancer

“…SETDB1 immunohistochemistry correlated with clinical characteristics in one study (Kostaki et al, 2014), while a study with a similar approach identified prognostic significance for G9A (EHMT2), but not SETDB1 expression (Miura et al, 2014). A functional role for SETBP1 and SUV39 has also been proposed in glioma and prostate cancer (Spyropoulou et al, 2014;Sun et al, 2014). Modulation of H3K9 methylation is also a critical downstream mechanisms of mutant IDH in glioma (as discussed below), and the effect of MLLfusions and DOT1L in MLL-rearranged leukemias (as discussed above).…”