Skip to content
2000
image of A Prognostic Lysine Crotonylation Signature Shapes the Immune Microenvironment in Hepatocellular Carcinoma

Abstract

Introduction

Hepatocellular carcinoma (HCC) has a poor prognosis due to late diagnosis and rapid progression, highlighting the need for a deeper understanding of its pathogenesis. Lysine crotonylation (Kcr), a unique post-translational modification, plays a crucial role in epigenetic regulation. However, the role of crotonylation-related genes (CRGs) in HCC remains poorly understood, necessitating an investigation of their prognostic and therapeutic relevance.

Methods

Transcriptomic and clinical data were obtained from TCGA and GEO databases. A CRG-based risk score was developed using Cox and LASSO regression analyses. To enhance survival prediction, a nomogram incorporating the risk score was constructed. Immune cell infiltration and drug sensitivity were assessed using CIBERSORT and 'OncoPredict.' Single-cell sequencing was employed to examine CRG expression within the HCC tumor microenvironment.

Results

An 8-gene risk score model (HDAC2, ACADS, HDAC1, ENO1, PPARG, ACADL, ACSL6, and AGPAT5) was established, effectively stratifying patients into high- and low-risk groups in the training set. Cox regression and Kaplan-Meier analyses validated its prognostic value in the test set. The nomogram demonstrated enhanced prognostic accuracy for survival prediction. Differences in immune cell infiltration and immune checkpoint expression between risk groups highlighted the association between CRGs and the tumor immune microenvironment. Single-cell sequencing revealed that CRGs were highly expressed in key immune cells within the HCC microenvironment. Additionally, drug sensitivity analysis suggested that specific targeted therapies may be more effective in HCC patients.

Discussion

Crotonylation-related gene signature demonstrates strong prognostic value in hepatocellular carcinoma (HCC), effectively stratifying patients into high- and low-risk groups and recapitulating known oncogenic roles of HDAC1/2, ENO1, PPARG, AGPAT5 and the protective functions of ACADS, ACADL, and ACSL6. It was found that crotonylation not only influences tumor cell metabolism and epigenetic regulation but also shapes the immune microenvironment, highlighted by distinct checkpoint expression, differential immune cell infiltration, and drug sensitivity profiles, which position our model as a promising tool for personalized therapeutic decision-making. However, clinical translation will require standardized, reproducible assays for crotonylation measurement and rigorous validation across diverse HCC etiologies ( viral . non-viral), along with mechanistic and longitudinal studies to dissect causality correlation, assess off- target effects of crotonylation modulators, and confirm functional impacts on immune modulation before routine diagnostic or therapeutic use.

Conclusion

This study identifies a prognostic CRG signature for HCC and provides novel insights into personalized treatment strategies.

© 2025 Bentham Science Publishers
Loading

Article metrics loading...

/content/journals/cmc/10.2174/0109298673381518250529110617
2025-06-13
2025-09-10

  • From This Site

    /content/journals/cmc/10.2174/0109298673381518250529110617
    dcterms_title,dcterms_subject,pub_keyword
    -contentType:Contributor -contentType:Concept -contentType:Institution
    10
    5
Loading full text...

Full text loading...

References

  1. Siegel R.L. Miller K.D. Wagle N.S. Jemal A. Cancer statistics, 2023. CA Cancer J. Clin. 2023 73 1 17 48 10.3322/caac.21763 36633525
    [Google Scholar]
  2. Su W. Zhou Y. Li X. Kang K. Nie H. Construction and validation of a novel butyrylation-related gene signature related to prognosis, clinical implications, and immune microenvironment characterization of hepatocellular carcinoma. ACS Omega 2025 10 4 3375 3388 10.1021/acsomega.4c06496 39926543
    [Google Scholar]
  3. Vogel A. Meyer T. Sapisochin G. Salem R. Saborowski A. Hepatocellular carcinoma. Lancet 2022 400 10360 1345 1362 10.1016/S0140‑6736(22)01200‑4 36084663
    [Google Scholar]
  4. Su W. Shi X. Wen X. Li X. Zhou J. Zhou Y. Ren F. Kang K. Integrative analysis of multiple cell death model for precise prognosis and drug response prediction in gastric cancer. Discov. Oncol. 2024 15 1 532 10.1007/s12672‑024‑01411‑4 39377861
    [Google Scholar]
  5. Sabari B.R. Zhang D. Allis C.D. Zhao Y. Metabolic regulation of gene expression through histone acylations. Nat. Rev. Mol. Cell Biol. 2017 18 2 90 101 10.1038/nrm.2016.140 27924077
    [Google Scholar]
  6. Xu W. Wan J. Zhan J. Li X. He H. Shi Z. Zhang H. Global profiling of crotonylation on non-histone proteins. Cell Res. 2017 27 7 946 949 10.1038/cr.2017.60 28429772
    [Google Scholar]
  7. Wu Q. Li W. Wang C. Fan P. Cao L. Wu Z. Wang F. Ultradeep Lysine crotonylome reveals the crotonylation enhancement on both histones and nonhistone proteins by SAHA treatment. J. Proteome Res. 2017 16 10 3664 3671 10.1021/acs.jproteome.7b00380 28882038
    [Google Scholar]
  8. Simic Z. Weiwad M. Schierhorn A. Steegborn C. Schutkowski M. The ɛ-amino group of protein lysine residues is highly susceptible to nonenzymatic acylation by several physiological Acyl-CoA thioesters. ChemBioChem 2015 16 16 2337 2347 10.1002/cbic.201500364 26382620
    [Google Scholar]
  9. Yuan H. Wu X. Wu Q. Chatoff A. Megill E. Gao J. Huang T. Duan T. Yang K. Jin C. Yuan F. Wang S. Zhao L. Zinn P.O. Abdullah K.G. Zhao Y. Snyder N.W. Rich J.N. Lysine catabolism reprograms tumour immunity through histone crotonylation. Nature 2023 617 7962 818 826 10.1038/s41586‑023‑06061‑0 37198486
    [Google Scholar]
  10. Wei W. Mao A. Tang B. Zeng Q. Gao S. Liu X. Lu L. Li W. Du J.X. Li J. Wong J. Liao L. Large-scale identification of protein crotonylation reveals its role in multiple cellular functions. J. Proteome Res. 2017 16 4 1743 1752 10.1021/acs.jproteome.7b00012 28234478
    [Google Scholar]
  11. Suzuki Y. Horikoshi N. Kato D. Kurumizaka H. Crystal structure of the nucleosome containing histone H3 with crotonylated lysine 122. Biochem. Biophys. Res. Commun. 2016 469 3 483 489 10.1016/j.bbrc.2015.12.041 26694698
    [Google Scholar]
  12. Zhang D. Tang J. Xu Y. Huang X. Wang Y. Jin X. Wu G. Liu P. Global crotonylome reveals hypoxia-mediated lamin A crotonylation regulated by HDAC6 in liver cancer. Cell Death Dis. 2022 13 8 717 10.1038/s41419‑022‑05165‑1 35977926
    [Google Scholar]
  13. Zhang Y. Chen Y. Zhang Z. Tao X. Xu S. Zhang X. Zurashvili T. Lu Z. Bayascas J.R. Jin L. Zhao J. Zhou X. Acox2 is a regulator of lysine crotonylation that mediates hepatic metabolic homeostasis in mice. Cell Death Dis. 2022 13 3 279 10.1038/s41419‑022‑04725‑9 35351852
    [Google Scholar]
  14. Baumann K. Crotonylation versus acetylation. Nat. Rev. Mol. Cell Biol. 2015 16 5 265 10.1038/nrm3992 25907603
    [Google Scholar]
  15. Zheng Y. Zhu L. Qin Z.Y. Guo Y. Wang S. Xue M. Shen K.Y. Hu B.Y. Wang X.F. Wang C.Q. Qin L.X. Dong Q.Z. Modulation of cellular metabolism by protein crotonylation regulates pancreatic cancer progression. Cell Rep. 2023 42 7 112666 10.1016/j.celrep.2023.112666 37347667
    [Google Scholar]
  16. Rastin F. Oryani M.A. Iranpour S. Javid H. Hashemzadeh A. Karimi-Shahri M. A new era in cancer treatment: Harnessing ZIF-8 nanoparticles for PD-1 inhibitor delivery. J. Mater. Chem. B Mater. Biol. Med. 2024 12 4 872 894 10.1039/D3TB02471G 38193564
    [Google Scholar]
  17. Einafshar E. Javid H. Amiri H. Akbari-Zadeh H. Hashemy S.I. Curcumin loaded β-cyclodextrin-magnetic graphene oxide nanoparticles decorated with folic acid receptors as a new theranostic agent to improve prostate cancer treatment. Carbohydr. Polym. 2024 340 122328 10.1016/j.carbpol.2024.122328 38857995
    [Google Scholar]
  18. Zheng Z. Zhong Q. Yan X. YWHAE/14-3-3ε crotonylation regulates leucine deprivation-induced autophagy. Autophagy 2023 19 8 2401 2402 10.1080/15548627.2023.2166276 36628438
    [Google Scholar]
  19. Yan G. Li X. Zheng Z. Gao W. Chen C. Wang X. Cheng Z. Yu J. Zou G. Farooq M.Z. Zhu X. Zhu W. Zhong Q. Yan X. KAT7-mediated CANX (calnexin) crotonylation regulates leucine-stimulated MTORC1 activity. Autophagy 2022 18 12 2799 2816 10.1080/15548627.2022.2047481 35266843
    [Google Scholar]
  20. Hu X. Xing W. Zhao R. Tan Y. Wu X. Ao L. Li Z. Yao M. Yuan M. Guo W. Li S. Yu J. Ao X. Xu X. HDAC2 inhibits EMT-mediated cancer metastasis by downregulating the long noncoding RNA H19 in colorectal cancer. J. Exp. Clin. Cancer Res. 2020 39 1 270 10.1186/s13046‑020‑01783‑9 33267897
    [Google Scholar]
  21. Zhang Z. Qiu N. Yin J. Zhang J. Liu H. Guo W. Liu M. Liu T. Chen D. Luo K. Li H. He Z. Liu J. Zheng G. SRGN crosstalks with YAP to maintain chemoresistance and stemness in breast cancer cells by modulating HDAC2 expression. Theranostics 2020 10 10 4290 4307 10.7150/thno.41008 32292495
    [Google Scholar]
  22. Wang B. Shen X. Pan L. Li Z. Chen C. Yao Y. Tang D. Gao W. The HDAC2–MTA3 interaction induces nonsmall cell lung cancer cell migration and invasion by targeting c-Myc and cyclin D1. Mol. Carcinog. 2023 62 11 1630 1644 10.1002/mc.23604 37401867
    [Google Scholar]
  23. Qi Z.P. Yalikong A. Zhang J.W. Cai S.L. Li B. Di S. Lv Z.T. Xu E.P. Zhong Y.S. Zhou P.H. HDAC2 promotes the EMT of colorectal cancer cells and via the modular scaffold function of ENSG00000274093.1. J. Cell. Mol. Med. 2021 25 2 1190 1197 10.1111/jcmm.16186 33325150
    [Google Scholar]
  24. Rastin F. Javid H. Oryani M.A. Rezagholinejad N. Afshari A.R. Karimi-Shahri M. Immunotherapy for colorectal cancer: Rational strategies and novel therapeutic progress. Int. Immunopharmacol. 2024 126 111055 10.1016/j.intimp.2023.111055 37992445
    [Google Scholar]
  25. Javid H. Attarian F. Saadatmand T. Rezagholinejad N. Mehri A. Amiri H. Karimi-Shahri M. The therapeutic potential of immunotherapy in the treatment of breast cancer: Rational strategies and recent progress. J. Cell. Biochem. 2023 124 4 477 494 10.1002/jcb.30402 36966454
    [Google Scholar]
  26. Nagarajan S. Rao S.V. Sutton J. Cheeseman D. Dunn S. Papachristou E.K. Prada J.E.G. Couturier D.L. Kumar S. Kishore K. Chilamakuri C.S.R. Glont S.E. Archer Goode E. Brodie C. Guppy N. Natrajan R. Bruna A. Caldas C. Russell A. Siersbæk R. Yusa K. Chernukhin I. Carroll J.S. ARID1A influences HDAC1/BRD4 activity, intrinsic proliferative capacity and breast cancer treatment response. Nat. Genet. 2020 52 2 187 197 10.1038/s41588‑019‑0541‑5 31913353
    [Google Scholar]
  27. Jo H. Shim K. Kim H.U. Jung H.S. Jeoung D. HDAC2 as a target for developing anti-cancer drugs. Comput. Struct. Biotechnol. J. 2023 21 2048 2057 10.1016/j.csbj.2023.03.016 36968022
    [Google Scholar]
  28. Zhang T. Sun L. Hao Y. Suo C. Shen S. Wei H. Ma W. Zhang P. Wang T. Gu X. Li S.T. Chen Z. Yan R. Zhang Y. Cai Y. Zhou R. Jia W. Huang F. Gao P. Zhang H. ENO1 suppresses cancer cell ferroptosis by degrading the mRNA of iron regulatory protein 1. Nat. Cancer 2021 3 1 75 89 10.1038/s43018‑021‑00299‑1 35121990
    [Google Scholar]
  29. Sun M. Li L. Niu Y. Wang Y. Yan Q. Xie F. Qiao Y. Song J. Sun H. Li Z. Lai S. Chang H. Zhang H. Wang J. Yang C. Zhao H. Tan J. Li Y. Liu S. Lu B. Liu M. Kong G. Zhao Y. Zhang C. Lin S.H. Luo C. Zhang S. Shan C. PRMT6 promotes tumorigenicity and cisplatin response of lung cancer through triggering 6PGD/ENO1 mediated cell metabolism. Acta Pharm. Sin. B 2023 13 1 157 173 10.1016/j.apsb.2022.05.019 36815049
    [Google Scholar]
  30. Song Q. Zhang K. Sun T. Xu C. Zhao W. Zhang Z. Knockout of ENO1 leads to metabolism reprogramming and tumor retardation in pancreatic cancer. Front. Oncol. 2023 13 1119886 10.3389/fonc.2023.1119886 36845730
    [Google Scholar]
  31. Tate T. Xiang T. Wobker S.E. Zhou M. Chen X. Kim H. Batourina E. Lin C.S. Kim W.Y. Lu C. Mckiernan J.M. Mendelsohn C.L. Pparg signaling controls bladder cancer subtype and immune exclusion. Nat. Commun. 2021 12 1 6160 10.1038/s41467‑021‑26421‑6 34697317
    [Google Scholar]
  32. Ogino S. Shima K. Baba Y. Nosho K. Irahara N. Kure S. Chen L. Toyoda S. Kirkner G.J. Wang Y.L. Giovannucci E.L. Fuchs C.S. Colorectal cancer expression of peroxisome proliferator-activated receptor gamma (PPARG, PPARgamma) is associated with good prognosis. Gastroenterology 2009 136 4 1242 1250 10.1053/j.gastro.2008.12.048 19186181
    [Google Scholar]
  33. Strembitska A. Labouèbe G. Picard A. Berney X.P. Tarussio D. Jan M. Thorens B. Lipid biosynthesis enzyme AGPAT5 in AgRP-neurons is required for insulin-induced hypoglycemia sensing and glucagon secretion. Nat. Commun. 2022 13 1 5761 10.1038/s41467‑022‑33484‑6 36180454
    [Google Scholar]
  34. Wen P. Wang R. Xing Y. Ouyang W. Yuan Y. Zhang S. Liu Y. Peng Z. The prognostic value of the GPAT/AGPAT gene family in hepatocellular carcinoma and its role in the tumor immune microenvironment. Front. Immunol. 2023 14 1026669 10.3389/fimmu.2023.1026669 36845084
    [Google Scholar]
/content/journals/cmc/10.2174/0109298673381518250529110617
Loading
A Prognostic Lysine Crotonylation Signature Shapes the Immune Microenvironment in Hepatocellular Carcinoma
Bentham Science Publishers ; https://doi.org/10.2174/0109298673381518250529110617
/content/journals/cmc/10.2174/0109298673381518250529110617
/content/journals/cmc/10.2174/0109298673381518250529110617
Loading

Data & Media loading...

Supplements

Supplementary material is available on the publisher’s website along with the published article.

file format download Download

  • Article Type:     Research Article
Keywords: Hepatocellular carcinoma ; lysine crotonylation ; TCGA database ; drug sensitivity ; tumor microenvironment ; prognostic model

Most Cited Most Cited RSS feed

This is a required field
Please enter a valid email address
Approval was a Success
Invalid data
An Error Occurred
Approval was partially successful, following selected items could not be processed due to error
Please enter a valid_number test