Nonhistone protein acetylation as cancer therapy targets

Singh, Brahma N.; Zhang, Guanghua; Hwa, Yi L.; Li, Jinping; Dowdy, Sean C.; Jiang, Shi Wen

doi:10.1586/era.10.62

Cited by 257 publications

(203 citation statements)

References 186 publications

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“…In general, acetylation of histones H3 and H4 correlates with regulation of gene transcriptional activation (Dhalluin et al, 1999). Aberrant acetylation modification of some nonhistones such as p53, NF-κB/ p65, CBP, p300, STAT3, tubulin, GATA factors, nuclear receptors, c-Myc, HIF-1α and FoxO1, Rb et al, is also relevant with tumorigenesis (Singh et al, 2010;Khan et al, 2013). Hyperacetylation mediated by HAT is an important way to activate oncogene (Dicerbo et al, 2013).…”

Section: Discussionmentioning

confidence: 99%

“…Disorders and imbalances of oncogenes and tumor suppressor genes are closely related to abnormal histone acetylation modifications in a growing number of malignancies including breast cancer. An increasing number of studies also demonstrated that some abnormal nonhistone acetylation modification plays a crucial role in cancer development and progression (Singh et al, 2010;Mooney et al, 2010).…”

Section: Introductionmentioning

confidence: 99%

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Garcinol, an Acetyltransferase Inhibitor, Suppresses Proliferation of Breast Cancer Cell Line MCF-7 Promoted by 17β-Estradiol

Xia¹,

Liu²,

Zhang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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The acetyltransferase inhibitor garcinol, a polyisoprenylated benzophenone, is extracted from the rind of the fruit of Garcinia indica, a plant found extensively in tropical regions. Anti-cancer activity has been suggested but there is no report on its action via inhibiting acetylation against cell proliferation, cell cycle progression, and apoptosis-inhibtion induced by estradiol (E 2 ) in human breast cancer MCF-7 cells. The main purposes of this study were to investigate the effects of the acetyltransferase inhibitor garcinol on cell proliferation, cell cycle progression and apoptosis inhibition in human breast cancer MCF-7 cells treated with estrogen, and to explore the significance of changes in acetylation levels in this process. We used a variety of techniques such as CCK-8 analysis of cell proliferation, FCM analysis of cell cycling and apoptosis, immunofluorescence analysis of NF-κB/ p65 localization, and RT-PCR and Western blotting analysis of ac-H3, ac-H4, ac-p65, cyclin D1, Bcl-2 and Bclxl. We found that on treatment with garcinol in MCF-7 cells, E 2 -induced proliferation was inhibited, cell cycle progression was arrested at G0/G1 phase, and the cell apoptosis rate was increased. Expression of ac-H3, ac-H4 and NF-κB/ac-p65 proteins in E 2 -treated MCF-7 cells was increased, this being inhibited by garcinol but not ac-H4.The nuclear translocation of NF-κB/p65 in E 2 -treated MCF-7 cells was also inhibited, along with cyclin D1, Bcl-2 and Bcl-xl in mRNA and protein expression levels. These results suggest that the effect of E 2 on promoting proliferation and inhibiting apoptosis is linked to hyperacetylation levels of histones and nonhistone NF-κB/ p65 in MCF-7 cells. The acetyltransferase inhibitor garcinol plays an inhibitive role in MCF-7 cell proliferation promoted by E 2 . Mechanisms are probably associated with decreasing ac-p65 protein expression level in the NF-κB pathway, thus down-regulating the expression of cyclin D1, Bcl-2 and Bcl-xl.

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Section: Discussionmentioning

confidence: 99%

Section: Introductionmentioning

confidence: 99%

Garcinol, an Acetyltransferase Inhibitor, Suppresses Proliferation of Breast Cancer Cell Line MCF-7 Promoted by 17β-Estradiol

Xia¹,

Liu²,

Zhang³

et al. 2014

Asian Pacific Journal of Cancer Prevention

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“…17,18 Other than chromatin proteins, transcription factors and cell-signaling regulatory proteins could also be the substrates for HDACs. 19 Particularly, HDAC superfamily has been receiving increasing attention for its role in modulating both innate and adaptive immune responses 20,21 implicatd in allograft survival and transplantation outcome. 22 As such, HDAC inhibitors (HDACis) are now under intensive study for their feasibility as potential anti-rejection agents.…”

Section: Introductionmentioning

confidence: 99%

SAHA, an HDAC inhibitor, synergizes with tacrolimus to prevent murine cardiac allograft rejection

et al. 2012

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Suberoylanilide hydroxamic acid (SAHA), as a histone deacetylase (HDAC) inhibitor (HDACi), was recently found to exhibit an immunosuppressive effect. However, whether SAHA can synergize with calcineurin inhibitors (CNIs) to inhibit allograft rejection and its underlying mechanism remain elusive. In this study, we demonstrated the synergistic effects of SAHA and non-therapeutic dose of tacrolimus (FK506) in prolonging the allograft survival in a murine cardiac transplant model. Concomitant intragraft examination revealed that allografts from SAHA-treated recipients showed significantly lower levels of IL-17 expression, and no discernable difference for IL-17 expressions was detected between SAHA-and SAHA/FK506-treated allograft as compared with allografts from FK506-treated animals. In contrast, administration of FK506 significantly suppressed interferon (IFN)-c but increased IL-10 expression as compared with that of SAHA-treated animals, and this effect was independent of SAHA. Interestingly, SAHA synergizes with FK506 to promote Foxp3 and CTLA4 expression. In vitro, SAHA reduced the proportion of Th17 cells in isolated CD4 1 T-cell population and decreased expressions of IL-17A, IL-17F, STAT3 and RORct in these cells. Moreover, SAHA enhances suppressive function of regulatory T (Treg) cells by upregulating the expression of CTLA-4 without affecting T effector cell proliferation, and increased the proportion of Treg by selectively promoting apoptosis of T effector cells. Therefore, SAHA, a HDACi, may be a promising immunosuppressive agent with potential benefit in conjunction with CNI drugs.

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“…Reversible lysine acetylation in these proteins regulates cellular processes such as the control of mRNA stability, protein localization and degradation, protein-protein as well as protein-DNA interactions [36]. Recently, Grabiec et al reported that the HDAC inhibitors TSA and ITF2357 reduced IL6 mRNA stability in macrophages and RASF.…”

Section: Histone Acetylationmentioning

confidence: 99%

Epigenetic modifications in rheumatoid arthritis, a review

Klein

Gay

2013

Current Opinion in Pharmacology

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Rheumatoid arthritis is an autoimmune disease characterized by chronic joint inflammation and progressive destruction of cartilage and bone which leads to ultimately loss of function and pain. Activated synovial fibroblasts are key effector cells in the pathogenesis of rheumatoid arthritis. In the recent years, epigenetic changes including DNA methylation, histone acetylation and other histone modifications were identified that are associated with an intrinsic activation and the aggressive phenotype of these cells. So far, no therapies targeting rheumatoid arthritis synovial fibroblasts exist. This review comprises recent research efforts that propose epigenetic mechanisms behind the activation of rheumatoid arthritis synovial fibroblasts and other cell types. This review comprises recent research efforts that reveal the mechanisms behind the intrinsic activation of RASF by investigating epigenetic changes ( Figure 1) and summarizes data available from other cell types. What is epigenetics?Originally, epigenetic mechanisms were considered as heritable changes in gene function that were not explainable by changes in the DNA sequence. A more revised definition of epigenetics is the structural adaption of chromosomal regions in order to register, signal or perpetuate altered activity states [3]. Epigenetic modifications including DNA methylation and covalent histone modifications such as acetylation, methylation and ubiquitination alter the accessibility of DNA to the transcription machinery. An increasing amount of proteins that attach ("writers") or remove ("erasers") modifications to DNA and histones or that bind ("readers") to a specific epigenetically modified site have emerged as key players in the regulation of gene expression [4]. Most chromatin marks are highly dynamic and have the capability of influencing transcription by multiple mechanisms; first, they designate chromatin structure and therefore, determine the accessibility of DNA for regulatory proteins; second, they recruit remodeling enzymes that utilize the hydrolysis of ATP to reposition nucleosomes; and third, they mediate the cooperation between pioneer and secondary transcription factors Histone acetylation on lysines is regulated by the opposing activity of two enzyme families, histone acetyl transferases (HATs) and histone deacetylases (HDACs). Histone acetylation neutralizes lysine`s positive charges, an action that has the potential to weaken the interactions between DNA and histones. HDACs are thought to stabilize the local chromatin structure by restoring the positive charges in lysine residues. Therefore, they are mainly considered as transcriptional repressors [5].Unlike acetylation, histone methylation does not alter the charge of histone proteins. Histone methylation mainly occurs at lysine and arginine residues of histones H3 and H4 which can be mono-, di-(lysines, arginines) and trimethylated (lysines) [5]. Depending on the position and the degree of methylation, histone methylation marks can be associated with transcripti...

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Nonhistone protein acetylation as cancer therapy targets

Cited by 257 publications

References 186 publications

Garcinol, an Acetyltransferase Inhibitor, Suppresses Proliferation of Breast Cancer Cell Line MCF-7 Promoted by 17β-Estradiol

Garcinol, an Acetyltransferase Inhibitor, Suppresses Proliferation of Breast Cancer Cell Line MCF-7 Promoted by 17β-Estradiol

SAHA, an HDAC inhibitor, synergizes with tacrolimus to prevent murine cardiac allograft rejection

Epigenetic modifications in rheumatoid arthritis, a review

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