Transcriptional regulation of 15-lipoxygenase expression by promoter methylation

Liu, Cheng; Xu, Dawei; Sjøberg, Jan; Forsell, Pontus; Björkholm, Magnus; Claesson, Hans‐Erik

doi:10.1016/j.yexcr.2004.02.014

Cited by 61 publications

(56 citation statements)

References 29 publications

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“…In addition, Shankaranarayanan et al (24) obtained evidence that acetylation of both histones and STAT6 seem to be necessary for the transcriptional activity of 15-LOX-1 in A549 cells. Furthermore, recent studies indicate that the 15-LOX-1 promoter is hypermethylated in several types of cancer (25). Therefore, in future studies, it will also be of interest to determine whether PKG activation enhances the expression of 15-LOX-1 by producing localized changes in chromatin structure.…”

Section: Discussionmentioning

confidence: 99%

Activation of Protein Kinase G Up-regulates Expression of 15-Lipoxygenase-1 in Human Colon Cancer Cells

Deguchi

Xing

Shureiqi³

et al. 2005

Cancer Research

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Recent studies indicate that the induction of apoptosis in human colon cancer cells by certain nonsteroidal antiinflammatory drugs involves increased expression of 15-LOX-1 and synthesis of its major product 13-S-hydroxyoctadecadienoic acid (13-S-HODE). Evidence was obtained that this occurs via a cyclooxygenase-2 (COX-2)-independent mechanism, but the actual mechanism of induction of 15-LOX-1 by these compounds is not known. There is extensive evidence that treatment of SW480 human colon cancer cells with sulindac sulfone (Exisulind, Aptosyn) or the related derivative OSI-461, both of which inhibit cyclic GMP (cGMP)-phosphodiesterases but lack COX-2 inhibitory activity, causes an increase in intracellular levels of cGMP, thus activating protein kinase G (PKG), which then activates pathways that lead to apoptosis. Therefore, in the present study, we examined the effects of various agents that cause increased cellular levels of cGMP on the expression of 15-LOX-1 in SW480 human colon cancer cells. Treatment of the cells with Exisulind, sulindac sulfide, OSI-461, the guanylyl cyclase activator YC-1, or the cell-permeable cGMP compound 8-para-chlorophenylthio-cGMP (8-pCPT-cGMP) caused an increase in cellular levels of 15-LOX-1. Exisulind, OSI-461, and 8-pCPT-cGMP also increased mRNA levels of 15-LOX-1, suggesting that the effects were at the level of transcription. The cGMP-phosphodiesterase inhibitors and YC-1 increased the production of 13-S-HODE, which is the linoleic acid metabolite of 15-LOX-1. Treatment of SW480 cells with the PKG inhibitor Rp-8-pCPT-cGMP blocked Exisulindinduced 15-LOX-1 expression. Furthermore, derivatives of SW480 cells that were engineered to stably overexpress wildtype PKG IB displayed increased cellular levels of 15-LOX-1 when compared with vector control cells. Taken together, these results provide evidence that the cGMP/PKG pathway can play an important role in the induction of 15-LOX-1 expression by nonsteroidal antiinflammatory drugs and related agents. (Cancer Res 2005; 65(18): 8442-47)

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Section: Discussionmentioning

confidence: 99%

Activation of Protein Kinase G Up-regulates Expression of 15-Lipoxygenase-1 in Human Colon Cancer Cells

Deguchi

Xing

Shureiqi³

et al. 2005

Cancer Research

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“…Reversal of 15-LOX-1 transcriptional silencing in cancer cells has been proposed to occur via various mechanisms: global histone H4 (H4) acetylation (28), STAT-6 acetylation and phosphorylation (33), inhibition of GATA-6 transcriptional repression of the 15-LOX-1 promoter (29, 34), and 15-LOX-1 promoter DNA demethylation (30,35). Nonetheless, the exact mechanisms underlying 15-LOX-1 transcriptional reactivation in cancer cells remain unknown.…”

Section: -Lipoxygenase-1 (15-lox-1)mentioning

confidence: 99%

Chromatin Modification Requirements for 15-Lipoxygenase-1 Transcriptional Reactivation in Colon Cancer Cells

Zuo

Morris

Shureiqi

2008

Journal of Biological Chemistry

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15-Lipoxygenase-1 (15-LOX-1) contributes significantly to inflammation regulation and terminal cell differentiation. 15-LOX-1 is transcriptionally silenced in cancer cells, and its transcriptional reactivation (e.g. via histone deacetylase inhibitors (HDACIs)) is essential for restoring terminal cell differentiation to cancer cells. STAT-6 acetylation via the histone acetyltransferase KAT3B has been proposed to be necessary for 15-LOX-1 transcriptional activation. However, the exact mechanism underlying 15-LOX-1 transcriptional reactivation in cancer cells is still undefined, especially in regard to the contribution of 15-LOX-1 promoter histone modifications. We therefore examined the relative mechanistic contributions of 15-LOX-1 promoter histone modifications and STAT-6 to 15-LOX-1 transcriptional reactivation by HDACIs in colon cancer cells. We found that: 1) histone H3 and H4 acetylation in the 15-LOX-1 promoter through KAT3B was critical to 15-LOX-1 transcriptional activation; 2) 15-LOX-1 transcription was activated independently from STAT-6; and 3) dimethyl-histone H3 lysine 9 (H3K9me2) demethylation in the 15-LOX-1 promoter via the histone lysine demethylase KDM3A was an early and specific histone modification and was necessary for activation of transcription. These findings demonstrate that histone modification in the 15-LOX-1 promoter is important to 15-LOX-1 transcriptional silencing in colon cancer cells and that HDACIs can activate gene transcription via KDM3A demethylation of H3K9me2. 15-Lipoxygenase-1 (15-LOX-1)2 is a critical enzyme for the production of various inflammation-regulatory lipid signaling mediators, including 13-S-hydroxyoctadecadienoic acid from linoleic acid (1, 2), lipoxins from arachidonic acid (3), and resolvins and protectins from docosahexaenoic acid (4). 15-LOX-1 has an important regulatory function in terminal cell differentiation (5-11) and inflammation (3, 12), and its expression is inducible and highly regulated in normal human cells (13). 15-LOX-1 is down-regulated in various human cancers, including colon cancer (14 -16), esophageal cancer (17), breast cancer (18), and pancreatic cancer (19). 15-LOX-1 re-expression in cancer cells via pharmaceutical agents or plasmid or adenoviral vectors induces growth inhibition and re-establishes terminal cell differentiation and apoptosis (10, 15-17, 20 -26).15-LOX-1 expression, regulated at the translational level in normal cells (27), is transcriptionally silenced in cancer cells (28 -32). Reversal of 15-LOX-1 transcriptional silencing in cancer cells has been proposed to occur via various mechanisms: global histone H4 (H4) acetylation (28), STAT-6 acetylation and phosphorylation (33), inhibition of GATA-6 transcriptional repression of the 15-LOX-1 promoter (29, 34), and 15-LOX-1 promoter DNA demethylation (30,35). Nonetheless, the exact mechanisms underlying 15-LOX-1 transcriptional reactivation in cancer cells remain unknown. For example, it is unclear whether global H4 acetylation activates 15-LOX-1 transcription through direct ...

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“…5-Methylcytosine (5mC) is elevated in the intima of ApoE -/-mice fed a Western diet, and high 5mC levels are linked to LDL receptor and p53 mutation in vascular cells (43,46). 15-Lipoxygenase, a gene implicated in oxidative modification of LDL, is also regulated by DNA methylation (47). It is unknown, however, whether the proatherogenic mechanical force caused by d-flow regulates epigenetic DNA methylation.…”

Section: Introductionmentioning

confidence: 99%

Flow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosis

Dunn¹,

Qiu²,

Kim³

et al. 2014

J. Clin. Invest.

263

234

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Transcriptional regulation of 15-lipoxygenase expression by promoter methylation

Cited by 61 publications

References 29 publications

Activation of Protein Kinase G Up-regulates Expression of 15-Lipoxygenase-1 in Human Colon Cancer Cells

Activation of Protein Kinase G Up-regulates Expression of 15-Lipoxygenase-1 in Human Colon Cancer Cells

Chromatin Modification Requirements for 15-Lipoxygenase-1 Transcriptional Reactivation in Colon Cancer Cells

Flow-dependent epigenetic DNA methylation regulates endothelial gene expression and atherosclerosis

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