Global crotonylome reveals hypoxia-mediated lamin A crotonylation regulated by HDAC6 in liver cancer

Zhang, Dan; Tang, Jing; Xu, Yunhong; Huang, Xiaoju; Wang, Yilin; Jin, Xin; Wu, Gang; Liu, Pian

doi:10.1038/s41419-022-05165-1

Cited by 16 publications

(15 citation statements)

References 31 publications

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“…Wei W et al reported that the decrotonylase activity of crotonylated HDAC1 was lower than that of unmodi ed onces [32]. Dan Zhang et al reported that crotonylation of lamin A at the site of K265/270 maintained its subcellular position, promoted liver cancer cell proliferation [22]. In the present study, PPI analyses showed that most of the identi ed non-histone crotonylated proteins in OSCC were closely connected to glycolysis, including PGK1, ALDOA, ENO1 and PFK.…”

Section: Discussionsupporting

confidence: 49%

Large-scale identification of lysine crotonylation reveals its potential role in oral squamous cell carcinoma

Yin

Zheng

Wang

et al. 2023

Preprint

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Background Lysine crotonylation, a newly identified type of posttranslational modification, has been implicated in the regulation of various biological processes. However, its role in oral squamous cell carcinoma (OSCC) remains unknown. The study aimed to reveal the global crotonylome in OSCC under hypoxic conditions and explore the potential underlying regulatory mechanism of crotonylation in OSCC. Methods Liquid-chromatography fractionation, affinity enrichment of crotonylated peptides and high-resolution mass spectrometry were used to detect differential crotonylation in CAL27 cells cultured under hypoxia. The obtained data were further analyzed through bioinformatics analysis to reveal the involved biological processes and pathways of the dysregulated crotonylated proteins. A site-mutated plasmid was used to investigate the effect of crotonylation on Heat Shock Protein 90 Alpha Family Class B Member 1 (HAP90AB1) function. Results The large-scale of crotonylome analysis revealed 1563 crotonylated modification sites on 605 proteins in CAL27 cells under hypoxia. Bioinformatics analysis showed that histone contonylation levels decreased while up-regulated crotonylated proteins were mainly concentrated in non-histone proteins. Notably, glycolysis-related proteins were prominently up-regulated among the identified crotonylated proteins, with HSP90AB1 having the most significant changes. Further experimental results confirmed that mutating lysine 265 of HSP90AB1 into a silent arginine weakened its function in promoting glycolysis. Conclusion Our study mapped the crotonylation modification of proteins under hypoxia in OSCC and uncovered the biological processes and pathways of the dysregulated crotonylated proteins. Crotonylation of HSP90AB1 in hypoxic conditions may promote the glycolysis regulation ability in OSCC, providing novel insights into the regulatory mechanism of crotonylation in OSCC under hypoxia and potential therapeutic targets for OSCC treatment.

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Section: Discussionsupporting

confidence: 49%

Large-scale identification of lysine crotonylation reveals its potential role in oral squamous cell carcinoma

Yin

Zheng

Wang

et al. 2023

Preprint

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“…Crotonylation can be reversibly catalyzed by HCT and histone decrotonylase (HDCR). In addition, HATs have also been shown to have HCT activity, and HDACs were reported to have HDCR activity 159–161 . The Taf14 protein containing the YEATS domain is a specific presence as a histone crotonylation modification “reader,” 162,163 laying a foundation for elucidating the biological function of Kcr.…”

Section: Ptms Of Histonesmentioning

confidence: 99%

Post‐translational modifications of histones: Mechanisms, biological functions, and therapeutic targets

Liu

Guo

et al. 2023

MedComm

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Histones are DNA‐binding basic proteins found in chromosomes. After the histone translation, its amino tail undergoes various modifications, such as methylation, acetylation, phosphorylation, ubiquitination, malonylation, propionylation, butyrylation, crotonylation, and lactylation, which together constitute the “histone code.” The relationship between their combination and biological function can be used as an important epigenetic marker. Methylation and demethylation of the same histone residue, acetylation and deacetylation, phosphorylation and dephosphorylation, and even methylation and acetylation between different histone residues cooperate or antagonize with each other, forming a complex network. Histone‐modifying enzymes, which cause numerous histone codes, have become a hot topic in the research on cancer therapeutic targets. Therefore, a thorough understanding of the role of histone post‐translational modifications (PTMs) in cell life activities is very important for preventing and treating human diseases. In this review, several most thoroughly studied and newly discovered histone PTMs are introduced. Furthermore, we focus on the histone‐modifying enzymes with carcinogenic potential, their abnormal modification sites in various tumors, and multiple essential molecular regulation mechanism. Finally, we summarize the missing areas of the current research and point out the direction of future research. We hope to provide a comprehensive understanding and promote further research in this field.

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“…False discovery rate (FDR) thresholds for protein, peptide, and modification sites were specified at 1% for targets (protein, peptide, and modification sites). Cutoffs for significant fold changes between cells by histone crotonylation were set as quantification ratios above 1.5 or below 0.67 (Yang et al, 2021;Zhang et al, 2022).…”

Section: Liquid Chromatography Tandem Mass Spectrometry (Lc-ms/ms)mentioning

confidence: 99%

“…The FDR values of the spectrogram, peptide, and protein identification were all less than 0.01. Identified protein had at least one unique peptide (Yang et al, 2021;Zhang et al, 2022).…”

Section: Database Searchmentioning

confidence: 99%

Folate-deficiency induced acyl-CoA synthetase short-chain family member 2 increases lysine crotonylome involved in neural tube defects

Wang

Zeng

et al. 2023

Front. Mol. Neurosci.

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Maternal folate deficiency increases the risk of neural tube defects (NTDs), but the mechanism remains unclear. Here, we established a mouse model of NTDs via low folate diets combined with MTX-induced conditions. We found that a significant increase in butyrate acid was observed in mouse NTDs brains. In addition, aberrant key crotonyl-CoA-producing enzymes acyl-CoA synthetase short-chain family member 2 (ACSS2) levels and lysine crotonylation (Kcr) were elevated high in corresponding low folate content maternal serum samples from mouse NTD model. Next, proteomic analysis revealed that folate deficiency led to global proteomic modulation, especially in key crotonyl-CoA-producing enzymes, and dramatic ultrastructural changes in mouse embryonic stem cells (mESCs). Furthermore, we determined that folate deficiency induced ACSS2 and Kcr in mESCs. Surprisingly, folic acid supplementation restored level of ACSS2 and Kcr. We also investigated overall protein post-translational Kcr under folate deficiency, revealing the key regulation of Kcr in glycolysis/gluconeogenesis, and the citric acid cycle. Our findings suggest folate deficiency leads to the occurrence of NTDs by altering ACSS2. Protein crotonylation may be the molecular basis for NTDs remodeling by folate deficiency.

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Global crotonylome reveals hypoxia-mediated lamin A crotonylation regulated by HDAC6 in liver cancer

Cited by 16 publications

References 31 publications

Large-scale identification of lysine crotonylation reveals its potential role in oral squamous cell carcinoma

Large-scale identification of lysine crotonylation reveals its potential role in oral squamous cell carcinoma

Post‐translational modifications of histones: Mechanisms, biological functions, and therapeutic targets

Folate-deficiency induced acyl-CoA synthetase short-chain family member 2 increases lysine crotonylome involved in neural tube defects

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