Lysine acetyltransferases and lysine deacetylases as targets for cardiovascular disease

Li, Peng; Ge, Junbo; Li, Hua

doi:10.1038/s41569-019-0235-9

Cited by 172 publications

(132 citation statements)

References 198 publications

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“…Epigenetic regulators have been reported to be essential for the initiation and progress of cardiac hypertrophy. For instance, the histone deacetylase (HDACs) and Sirtuins participated in cardiac hypertrophy by targeting histone and non-histone targets (Li et al, 2019). The histone demethylase family is also critically involved in pathological cardiac hypertrophy.…”

Section: Discussionmentioning

confidence: 99%

The Histone Demethylase JMJD1C Regulates CAMKK2-AMPK Signaling to Participate in Cardiac Hypertrophy

Zhao

et al. 2020

Front. Physiol.

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The roles of the histone demethylase JMJD1C in cardiac hypertrophy remain unknown. JMJD1C was overexpressed in hypertrophic hearts of humans and mice, whereas the histone methylation was reduced. Jmjd1c knockdown repressed the angiotensin II (Ang II)-mediated increase in cardiomyocyte size and overexpression of hypertrophic genes in cardiomyocytes. By contrast, JMJD1C overexpression promoted the hypertrophic response of cardiomyocytes. Our further molecular mechanism study revealed that JMJD1C regulated AMP-dependent kinase (AMPK) in cardiomyocytes. JMJD1C did not influence LKB1 but repressed Camkk2 expression in cardiomyocytes. Inhibition of CAMKK2 with STO609 blocked the effects of JMJD1C on AMPK. AMPK knockdown blocked the inhibitory functions of JMJD1C knockdown on Ang II-induced hypertrophic response, whereas metformin reduced the functions of JMJD1C and repressed the hypertrophic response in cardiomyocytes.

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Section: Discussionmentioning

confidence: 99%

The Histone Demethylase JMJD1C Regulates CAMKK2-AMPK Signaling to Participate in Cardiac Hypertrophy

Zhao

et al. 2020

Front. Physiol.

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“…Numerous studies had identified that deregulated acetylation is associated with various human diseases including developmental disorders, inflammation, immunity, neurological disorders, metabolic diseases and cancers. Thus, protein acetylation had been considered as attractive therapeutic targets, and small molecular inhibitors of KDACs, KATs and bromodomain proteins (acetyl-lysine readers) have emerged as attractive therapeutic candidates 30 , 31 , and some of which have been assessed in the clinic as therapies for diseases like advanced leukaemia, myelodysplastic syndromes, neurological diseases and immune disorders. HDACis like vorinostat, belinostat, panobinostat, romidepsin, valproic acid and sodium butyrate have been approved by FDA for the treatment of cutaneous T cell lymphoma, peripheral T cell lymphoma, multiple myeloma or neurological disorders 30 , 32 , 33 .…”

Section: Discussionmentioning

confidence: 99%

“…Thus, protein acetylation had been considered as attractive therapeutic targets, and small molecular inhibitors of KDACs, KATs and bromodomain proteins (acetyl-lysine readers) have emerged as attractive therapeutic candidates 30 , 31 , and some of which have been assessed in the clinic as therapies for diseases like advanced leukaemia, myelodysplastic syndromes, neurological diseases and immune disorders. HDACis like vorinostat, belinostat, panobinostat, romidepsin, valproic acid and sodium butyrate have been approved by FDA for the treatment of cutaneous T cell lymphoma, peripheral T cell lymphoma, multiple myeloma or neurological disorders 30 , 32 , 33 . SA and C646 are both specific small molecular inhibitors of p300/CBP acting by inhibiting the acetyltransferase activity through binding with p300/CBP competing with acetyl-CoA directly 24 , 25 .…”

Section: Discussionmentioning

confidence: 99%

Acetylation dependent functions of Rab22a-NeoF1 Fusion Protein in Osteosarcoma

Liang

Wang

et al. 2020

Theranostics

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Background: Rab22a-NeoF1 fusion gene containing the 1-38aa of Rab22a (Rab22a 1-38 ) plays a decisive role in driving tumor metastasis by activating RhoA via binding to SmgGDS607. However, its intercellular regulation remains unknown. Methods: The Lys7 (K7) acetylation of Rab22a-NeoF1 was initially identified by mass spectrum. Co-transfection, immunoprecipitation and Western blotting were used to characterize the acetyltransferases and deacetylases responsible for the K7 acetylation of Rab22a-NeoF1, and to define the interaction of proteins. The specificity of K7 acetylation of Rab22a-NeoF1 was determined by its specific anti-K7ac-Rab22a-NeoF1 antibody and its K7R mutant. RhoA-GTP was measured by RhoA activation assay. The migration and invasion were assessed by Transwell assay without and with Matrigel matrix, respectively. The orthotopic osteosarcoma metastasis model in vivo was used to monitor the lung metastases of U2OS/MTX300-Luc stably expressing Vector, Rab22a-NeoF1 or its K7R mutant with or without C646, a relatively specific inhibitor of p300/CBP. The unpaired Student t test was used for the statistical significance. Results: The K7 of Rab22a-NeoF1 is acetylated by p300/CBP while is de-acetylated by both HDAC6 and SIRT1. The K7R mutant of Rab22a-NeoF1 lacks its binding to SmgGDS607 and subsequently lost its promoting functions, such as activation of RhoA, cell migration, invasion and lung metastasis in osteosarcoma in vitro and in viv o, which are also diminished by p300/CBP inhibitor C646. Conclusion: The promoting function of Rab22a-NeoF1 is dependent on its K7 acetylation in osteosarcoma, and targeting this acetylation (e.g., C646) may benefit cancer patients, in particular osteosarcoma patients, who are positive for the Rab22a 1-38 .

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“…Conversely, lysine deacetylation is catalyzed by KDACs, which comprise two major groups with distinct catalytic mechanisms: NAD + -dependent Sirtuins (SIRTs) and Zn 2+ -dependent histone deacetylases (HDACs) ( Figure 1 ). The acetylation levels of lysines are highly dynamic, and the balance between lysine acetylation and deacetylation is precisely controlled by KATs and KDACs as well as by the concentration of Ac-CoA in organellar compartments such as mitochondria [ 19 , 20 ].…”

Section: Lysine Acetylation and Its Regulatory Mechanism And Functmentioning

confidence: 99%

Imbalance of Lysine Acetylation Contributes to the Pathogenesis of Parkinson’s Disease

Wang

Sun

Wang

et al. 2020

IJMS

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Parkinson’s disease (PD) is one of the most common neurodegenerative disorders. The neuropathological features of PD are selective and progressive loss of dopaminergic neurons in the substantia nigra pars compacta, deficiencies in striatal dopamine levels, and the presence of intracellular Lewy bodies. Interactions among aging and genetic and environmental factors are considered to underlie the common etiology of PD, which involves multiple changes in cellular processes. Recent studies suggest that changes in lysine acetylation and deacetylation of many proteins, including histones and nonhistone proteins, might be tightly associated with PD pathogenesis. Here, we summarize the changes in lysine acetylation of both histones and nonhistone proteins, as well as the related lysine acetyltransferases (KATs) and lysine deacetylases (KDACs), in PD patients and various PD models. We discuss the potential roles and underlying mechanisms of these changes in PD and highlight that restoring the balance of lysine acetylation/deacetylation of histones and nonhistone proteins is critical for PD treatment. Finally, we discuss the advantages and disadvantages of different KAT/KDAC inhibitors or activators in the treatment of PD models and emphasize that SIRT1 and SIRT3 activators and SIRT2 inhibitors are the most promising effective therapeutics for PD.

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Lysine acetyltransferases and lysine deacetylases as targets for cardiovascular disease

Cited by 172 publications

References 198 publications

The Histone Demethylase JMJD1C Regulates CAMKK2-AMPK Signaling to Participate in Cardiac Hypertrophy

The Histone Demethylase JMJD1C Regulates CAMKK2-AMPK Signaling to Participate in Cardiac Hypertrophy

Acetylation dependent functions of Rab22a-NeoF1 Fusion Protein in Osteosarcoma

Imbalance of Lysine Acetylation Contributes to the Pathogenesis of Parkinson’s Disease

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