DZNep, inhibitor of S-adenosylhomocysteine hydrolase, down-regulates expression of SETDB1 H3K9me3 HMTase in human lung cancer cells

Lee, Ju-Kyung; Kim, Keun-Cheol

doi:10.1016/j.bbrc.2013.07.128

Cited by 70 publications

(51 citation statements)

References 27 publications

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“…3-Deazaneplanocin A (DZNep), an inhibitor of S-adenosylhomocysteine hydrolase that depletes PRC2 via an unclear mechanism, 44 demonstrated a tumor-suppressive effect in cancers including MLLrearranged leukemia 45 ; however, increasing evidence has indicated that DZNep lacks specificity. 46,47 Inhibitors highly selective to EZH2 [21][22][23] or to EZH2 and EZH1 25,48 have been discovered, some of which demonstrated early success in treating EZH2-mutated lymphoma 22 and SNF5-inactivated malignant rhabdoid tumors. 49 Furthermore, a hydrocarbon-stapled peptide (SAH-EZH2) has recently been developed to disrupt interaction of EED with EZH2 and EZH1, leading to degradation of PRC2.…”

Section: Discussionmentioning

confidence: 99%

Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia

et al. 2015

Blood

197

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Section: Discussionmentioning

confidence: 99%

Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia

et al. 2015

Blood

197

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“…Given that SAH is a potent inhibitor of the activity of several methyltransferases and that it also regulates the expression of methyltransferases at the transcriptional level, 15,27,28 we hypothesized that SAH accumulation-inhibited histone A, Representative micrographs of glucose-regulated protein-78 (GRP78) immunostaining in aortic sinuses of apoE −/− mice from the 4 groups (left) and quantification of the staining (right). B, Representative micrographs (left) and quantification (right) of CEBP-homologous protein (CHOP) immunostaining in aortic sinuses of apoE −/− mice from the 4 groups.…”

Section: Sah Accumulation Inhibits Histone Methylation Via the Inhibimentioning

confidence: 99%

“…The genes are mediated by SAH accumulation in human lung cancer cells. 28 To examine whether the inhibition of histone methylation by SAH accumulation is mediated by the inhibition of histone methyltransferases further, we assessed the total H3K9 methyltransferase activity and the mRNA expression of 4 H3K9 methyltransferases and analyzed the relationship between SAH and these enzymes. The results showed that the plasma SAH levels were negatively associated with the total H3K9 methyltransferase activity and the levels of mRNA for the H3K9 methyltransferases Suv39h1 and G9a (Figure 6).…”

Section: Xiao Et Al Sah and Atherosclerosis 67mentioning

confidence: 99%

“…Given that SAH is a potent inhibitor of the activity of several methyltransferases and that it also regulates the expression of methyltransferases at the transcriptional level, 15,27,28 we hypothesized that SAH accumulation-inhibited histone by guest on May 12, 2018 http://atvb.ahajournals.org/ Downloaded from methylation might be the result of inhibition of histone methyltransferases. As expected, the total H3K9 methyltransferase activity was significantly decreased by >50% in the ADA and SAHH shRNA groups when compared with those in the control group ( Figure 6A).…”

Section: Sah Accumulation Inhibits Histone Methylation Via the Inhibimentioning

confidence: 99%

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Increased Plasma S-Adenosylhomocysteine–Accelerated Atherosclerosis Is Associated With Epigenetic Regulation of Endoplasmic Reticulum Stress in apoE ^−/− Mice

Xiao

Huang

Zhang

et al. 2015

ATVB

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Objective-S-Adenosylhomocysteine (SAH) is a better predictor of cardiovascular disease than homocysteine is, and it has been implicated in mediating the pathogenicity of hyperhomocysteinemia in atherosclerosis via an epigenetic mechanism. However, the underlying mechanism remains unclear. Here, we tested the hypothesis whether the effect of SAH on atherosclerosis is involved in epigenetic regulation of endoplasmic reticulum stress. Approach and Results-A total of 48 apolipoprotein E-deficient mice at 8 weeks were randomly divided into 4 groups (n=12 for each group). The control group was fed a conventional diet, the adenosine dialdehyde group was fed a diet that was supplemented with the SAH hydrolase inhibitor adenosine dialdehyde, and the other 2 groups were intravenously injected with a retrovirus that expressed either SAH hydrolase short hairpin RNA or scrambled short hairpin RNA semiweekly for 16 weeks. Plasma SAH levels and atherosclerotic lesion size were significantly increased in adenosine dialdehyde and SAH hydrolase short hairpin RNA groups when compared with control group. Expression of endoplasmic reticulum stress markers glucose-regulated protein-78 and CEBP-homologous protein was significantly increased in the mice with elevated plasma SAH levels. Moreover, plasma SAH was negatively associated with a decrease in the expression of trimethylated histone H3 lysine 9 and histone methyltransferases. Chromatin immunoprecipitation assays showed a significant decrease in trimethylated histone H3 lysine 9 occupancy at the glucose-regulated protein-78 and CEBP-homologous protein promoters in mice treated with adenosine dialdehyde and SAH hydrolase short hairpin RNA when compared with control mice. Conclusions-Our results suggest that elevated plasma SAH levels-accelerated atherosclerosis was associated with the activation of endoplasmic reticulum stress via modulation of histone methylation. Xiao et al SAH and Atherosclerosis 61factor 6 also plays a key role in the production of chaperones that facilitate the repair process, including glucose-regulated protein-78 (GRP78). Upregulation of PKR-like ER kinase increases the levels of activating transcription factor 4 and CEBP-homologous protein (CHOP), a potent inducer of apoptosis.12 Numerous studies have shown that homocysteine may promote atherosclerosis through the activation of ER stress.13,14 However, there is no direct evidence that homocysteine, and not SAH, is responsible for this effect on ER stress, and no precise mechanisms have been described.SAH is produced as a product of methylation reactions involving S-adenosylmethionine (SAM) as the methyl donor, including the methylation of DNA, histone, and other proteins. 15 The ratio of SAM/SAH has been frequently used as an indicator of the cellular methylation potential. 16 Histones can be methylated on either lysine (K) or arginine (R) residues. Lysine residues can be monomethylated, dimethylated, or trimethylated in vivo. It has been reported that trimethylated histone H3 K4 (3meH3K4) is strongly ass...

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“…전사인자들은 DNA에 직접 작용하거나 RNA 중합효소의 결합력을 변화시켜 전사단계를 조절하는 등 RNA 합성을 증진 시키거나, 감소 시키는 역할을 수행한다 [1]. 따라서 유전자 발현을 연구하기 위해 프로모터 부위를 클로닝하여 luciferase 등과 같은 reporter 유전자 활성 등을 분석하는 실험들이 수행되고 있다 [10].…”

Section: 서 론unclassified

Promoter Cloning of Human SETDB1 Gene Utilizing Bioinformatic Programs

Noh¹,

Kim

2014

Journal of Life Science

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Eukaryotic gene expression is an important process, which is initiated by several transcription factors and RNA polymerases that occupy the promoter region of genomic DNA. Although there are many experiments to identify the promoter region in a gene, it is time and labor consuming to finalize it. In this study, we utilized bioinformatic programs, including Ensembl, NCBI, and CpG plots, to identify the cloning promoter region in SETDB1 genomic DNA. We performed PCR amplification to obtain the SETDB1 promoter on an approximately 2 kb region upstream from the TSS named SETDB1-P1. The PCR product was ligated with TA cloning vectors, and we confirmed the insert size using restriction enzyme digestion. Sequentially, the insert was subcloned into a pGL3-luc vector to produce pGL3-SETDB1-P1-luc and then confirmed by DNA sequencing. We also obtained a fragmented PCR product called P2 and P3 and performed a luciferase assay using pGL3-SETDB1-P1-luc transfection. We found that several anticancer drugs, including taxol, 4-FU, and doxorubicin, decreased the promoter activity of SETDB1. We obtained consistent data on the regulation of SETDB1 gene expression after anticancer drug treatment using Western blot analysis and RT-PCR. Our results suggest that promoter cloning of the human SETDB1 gene utilizing bioinformatics is a very useful and timesaving approach to study gene expression.

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DZNep, inhibitor of S-adenosylhomocysteine hydrolase, down-regulates expression of SETDB1 H3K9me3 HMTase in human lung cancer cells

Cited by 70 publications

References 27 publications

Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia

Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia

Increased Plasma S-Adenosylhomocysteine–Accelerated Atherosclerosis Is Associated With Epigenetic Regulation of Endoplasmic Reticulum Stress in apoE ^−/− Mice

Promoter Cloning of Human SETDB1 Gene Utilizing Bioinformatic Programs

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DZNep, inhibitor of S-adenosylhomocysteine hydrolase, down-regulates expression of SETDB1 H3K9me3 HMTase in human lung cancer cells

Cited by 70 publications

References 27 publications

Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia

Selective inhibition of EZH2 and EZH1 enzymatic activity by a small molecule suppresses MLL-rearranged leukemia

Increased Plasma S-Adenosylhomocysteine–Accelerated Atherosclerosis Is Associated With Epigenetic Regulation of Endoplasmic Reticulum Stress in apoE −/− Mice

Promoter Cloning of Human SETDB1 Gene Utilizing Bioinformatic Programs

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Increased Plasma S-Adenosylhomocysteine–Accelerated Atherosclerosis Is Associated With Epigenetic Regulation of Endoplasmic Reticulum Stress in apoE ^−/− Mice