Histone acetyltransferase 1 is a succinyltransferase for histones and non‐histones and promotes tumorigenesis

Yang, Guang; Yuan, Ying; Yuan, Hongfeng; Wang, Jiapei; Yun, Haolin; Geng, Yi; Zhao, Man; Li, Linhan; Weng, Yuhua; Liu, Zixian; Feng, Jinyan; Bu, Yanan; Liu, Lei; Wang, Bingnan; Zhang, Xiaodong

doi:10.15252/embr.202050967

Cited by 76 publications

(76 citation statements)

References 56 publications

(112 reference statements)

Supporting

Mentioning

Contrasting

Order By: Relevance

“…Multiple reports have suggested that HAT1 may be a cancer therapeutic target based on protein knockdowns or knockouts in various pre-clinical models. 2-5 These works, which include our own prior studies, motivated the search for small molecules capable of interfering with HAT1 enzymatic activity. We report here the development of a new approach to identify and characterize acetyltransferase activity based on a high-throughput, peptide-based, click-chemistry-enabled enzymatic assay.…”

Section: Discussionmentioning

confidence: 99%

An acetyl-click screening platform identifies a small molecule inhibitor of Histone Acetyltransferase 1 (HAT1) with anti-tumor activity

Gruber

Rangarajan

Chou

et al. 2021

Preprint

View full text Add to dashboard Cite

HAT1 is a central regulator of chromatin synthesis that acetylates nascent histone H3:H4 tetramers in the cytoplasm. It may have a role in cancer metabolism by linking cytoplasmic production of acetyl-CoA to nuclear acetyl flux. This is because the HAT1 di-acetylation mark is not propagated in chromatin and instead is de-acetylated after nascent histone insertion into chromatin. Thus, HAT1 likely provides a nuclear source of free acetate that may be recycled to acetyl-CoA for nuclear acetylation reactions. Correspondingly, suppression of HAT1 protein expression impairs tumor growth. To ascertain whether targeting HAT1 is a viable anti-cancer treatment strategy we sought to identify small molecule inhibitors of HAT1. We developed a high-throughput HAT1 acetyl-click assay to facilitate drug discovery and enzymology. Screening of small molecules computationally predicted to bind the active site led to the discovery of multiple riboflavin analogs that inhibited HAT1 enzymatic activity by competing with acetyl-CoA binding. These hits were refined by synthesis and testing over 70 analogs, which yielded structure-activity relationships. The isoalloxazine core was required for enzymatic inhibition, whereas modifications of the ribityl sidechain improved enzymatic potency and cellular growth suppression. These efforts resulted in a lead compound (JG-2016) that suppressed growth of human cancer cells lines in vitro and impaired tumor growth in vivo. This is the first report of a small molecule inhibitor of the HAT1 enzyme complex and represents a step towards targeting this pathway for cancer therapy.

show abstract

Section: Discussionmentioning

confidence: 99%

An acetyl-click screening platform identifies a small molecule inhibitor of Histone Acetyltransferase 1 (HAT1) with anti-tumor activity

Gruber

Rangarajan

Chou

et al. 2021

Preprint

View full text Add to dashboard Cite

show abstract

“…37 A recent study revealed that histone acetyltransferase 1 (HAT1) is a novel histone and non-histone succinyltransferase but does not participate with transferases of other PTMs, such as butyrylation and crotonylation, in HepG2 cells. 49 The study also suggested that HAT1 may be more likely to combine with succinyl-CoA than with acetyl-CoA. 49 In contrast, other findings show that enzymes may not play a central role in histone succinylation.…”

Section: Succinylation Of Lysine In Histonesmentioning

confidence: 98%

“…The mutation of tyrosine 645 in KAT2A ring 3 reduced H3 succinylation without changing H3 acetylation 37 . A recent study revealed that histone acetyltransferase 1 (HAT1) is a novel histone and non‐histone succinyltransferase but does not participate with transferases of other PTMs, such as butyrylation and crotonylation, in HepG2 cells 49 . The study also suggested that HAT1 may be more likely to combine with succinyl‐CoA than with acetyl‐CoA 49 …”

Section: The Structure and Function Of Histone Ksuc In The Nucleosomementioning

confidence: 99%

Histone succinylation and its function on the nucleosome

Liu

Shangguan

Tang

et al. 2021

J Cellular Molecular Medi

View full text Add to dashboard Cite

Protein post‐translational modifications (PTMs) of histones are ubiquitous regulatory mechanisms involved in many biological processes, including replication, transcription, DNA damage repair and ontogenesis. Recently, many short‐chain acylation histone modifications have been identified by mass spectrometry (MS). Lysine succinylation (Ksuc or Ksucc) is a newly identified histone PTM that changes the chemical environment of histones and is similar to other acylation modifications; lysine succinylation appears to accumulate at transcriptional start sites and to correlate with gene expression. Although numerous studies are ongoing, there is a lack of reviews on the Ksuc of histones. Here, we review lysine succinylation sites on histones, including the chemical characteristics and the mechanism by which lysine succinylation influences nucleosomal structure, chromatin dynamics and several diseases and then discuss lysine succinylation regulation to identify theoretical and experimental proof of Ksuc on histones and in diseases to inspire further research into histone lysine succinylation as a target of disease treatment in the future.

show abstract

“…Although widespread protein malonylation and succinylation have been described in the mitochondria ( 25 , 56 ), no specific succinyltransferases or malonytransferases have been identified to date. As a result, some researchers have proposed that non-enzymatic mechanisms may be responsible for such acyl modifications ( 55 ), while others suggest that some nuclear acetyltransferases, such as histone acetyltransferase 1 (HAT1), may be involved in nuclear protein lysine succinylation ( 57 ).…”

Section: The Process Of Protein Acetylationmentioning

confidence: 99%

Post-translational Acetylation Control of Cardiac Energy Metabolism

Ketema

Lopaschuk

2021

Front. Cardiovasc. Med.

View full text Add to dashboard Cite

Perturbations in myocardial energy substrate metabolism are key contributors to the pathogenesis of heart diseases. However, the underlying causes of these metabolic alterations remain poorly understood. Recently, post-translational acetylation-mediated modification of metabolic enzymes has emerged as one of the important regulatory mechanisms for these metabolic changes. Nevertheless, despite the growing reports of a large number of acetylated cardiac mitochondrial proteins involved in energy metabolism, the functional consequences of these acetylation changes and how they correlate to metabolic alterations and myocardial dysfunction are not clearly defined. This review summarizes the evidence for a role of cardiac mitochondrial protein acetylation in altering the function of major metabolic enzymes and myocardial energy metabolism in various cardiovascular disease conditions.

show abstract

Histone acetyltransferase 1 is a succinyltransferase for histones and non‐histones and promotes tumorigenesis

Cited by 76 publications

References 56 publications

An acetyl-click screening platform identifies a small molecule inhibitor of Histone Acetyltransferase 1 (HAT1) with anti-tumor activity

An acetyl-click screening platform identifies a small molecule inhibitor of Histone Acetyltransferase 1 (HAT1) with anti-tumor activity

Histone succinylation and its function on the nucleosome

Post-translational Acetylation Control of Cardiac Energy Metabolism

Contact Info

Product

Resources

About