Skip to main content
Top
Published in: BMC Cancer 1/2024

Open Access 01-12-2024 | Hepatocellular Carcinoma | Research

m1A regulator-mediated methylation modification patterns correlated with autophagy to predict the prognosis of hepatocellular carcinoma

Authors: Yingmin Wu, Lian Li, Long Wang, Shenjie Zhang, Zhirui zeng, Jieyu Lu, Zhi Wang, Yewei Zhang, Shilong Zhang, Haiyang Li, Tengxiang Chen

Published in: BMC Cancer | Issue 1/2024

Login to get access

Abstract

Background

N1-methyladenosine (m1A), among the most common internal modifications on RNAs, has a crucial role to play in cancer development. The purpose of this study were systematically investigate the modification characteristics of m1A in hepatocellular carcinoma (HCC) to unveil its potential as an anticancer target and to develop a model related to m1A modification characteristics with biological functions. This model could predict the prognosis for patients with HCC.

Methods

An integrated analysis of the TCGA-LIHC database was performed to explore the gene signatures and clinical relevance of 10 m1A regulators. Furthermore, the biological pathways regulated by m1A modification patterns were investigated. The risk model was established using the genes that showed differential expression (DEGs) between various m1A modification patterns and autophagy clusters. These in vitro experiments were subsequently designed to validate the role of m1A in HCC cell growth and autophagy. Immunohistochemistry was employed to assess m1A levels and the expression of DEGs from the risk model in HCC tissues and paracancer tissues using tissue microarray.

Results

The risk model, constructed from five DEGs (CDK5R2, TRIM36, DCAF8L, CYP26B, and PAGE1), exhibited significant prognostic value in predicting survival rates among individuals with HCC. Moreover, HCC tissues showed decreased levels of m1A compared to paracancer tissues. Furthermore, the low m1A level group indicated a poorer clinical outcome for patients with HCC. Additionally, m1A modification may positively influence autophagy regulation, thereby inhibiting HCC cells proliferation under nutrient deficiency conditions.

Conclusions

The risk model, comprising m1A regulators correlated with autophagy and constructed from five DEGs, could be instrumental in predicting HCC prognosis. The reduced level of m1A may represent a potential target for anti-HCC strategies.
Appendix
Available only for authorised users
Literature
1.
go back to reference Boccaletto P, Stefaniak F, Ray A, Cappannini A, Mukherjee S, Purta E, Kurkowska M, Shirvanizadeh N, Destefanis E, Groza P, et al. MODOMICS: a database of RNA modifification pathways. Nucleic Acids Res. 2022;50:D231–5.PubMedCrossRef Boccaletto P, Stefaniak F, Ray A, Cappannini A, Mukherjee S, Purta E, Kurkowska M, Shirvanizadeh N, Destefanis E, Groza P, et al. MODOMICS: a database of RNA modifification pathways. Nucleic Acids Res. 2022;50:D231–5.PubMedCrossRef
2.
go back to reference Dunn DB. The occurrence of 1-methyladenine in ribonucleic acid. Biochim Biophys Acta. 1961;46:198–200.PubMedCrossRef Dunn DB. The occurrence of 1-methyladenine in ribonucleic acid. Biochim Biophys Acta. 1961;46:198–200.PubMedCrossRef
3.
go back to reference Machnicka MA, Milanowska K, Osman Oglou O, Purta E, Kurkowska M, Olchowik A, Januszewski W, Kalinowski S, Dunin-Horkawicz S, Rother KM et al. MODOMICS: a database of RNA modification pathwaysd2013 update. Nucleic Acids Res. 2013; 41(Database issue): D262eD267. Machnicka MA, Milanowska K, Osman Oglou O, Purta E, Kurkowska M, Olchowik A, Januszewski W, Kalinowski S, Dunin-Horkawicz S, Rother KM et al. MODOMICS: a database of RNA modification pathwaysd2013 update. Nucleic Acids Res. 2013; 41(Database issue): D262eD267.
4.
go back to reference Xiong X, Li X, Yi C. N(1)-methyladenosine methylome in messenger RNA and non-coding RNA. Curr Opin Chem Biol. 2018;45:179e186.CrossRef Xiong X, Li X, Yi C. N(1)-methyladenosine methylome in messenger RNA and non-coding RNA. Curr Opin Chem Biol. 2018;45:179e186.CrossRef
5.
go back to reference Li X, Xiong X, Wang K, Wang L, Shu X, Ma S, Yi. C.Transcriptome-wide mapping reveals reversible and dynamic N(1)-methyladenosine methylome. Nat Chem Biol. 2016;12(5):311e316.CrossRef Li X, Xiong X, Wang K, Wang L, Shu X, Ma S, Yi. C.Transcriptome-wide mapping reveals reversible and dynamic N(1)-methyladenosine methylome. Nat Chem Biol. 2016;12(5):311e316.CrossRef
7.
go back to reference Xu GL, Bochtler M. Reversal of nucleobase methylation by dioxygenases. Nat Chem Biol. 2020;16:1160–9.PubMedCrossRef Xu GL, Bochtler M. Reversal of nucleobase methylation by dioxygenases. Nat Chem Biol. 2020;16:1160–9.PubMedCrossRef
8.
go back to reference Zhang C, Jia GF. Reversible RNA modification N1-methyladenosine (m1A) in mRNA and tRNA. Genomics Proteom Bioinf. 2018;16:155–61.CrossRef Zhang C, Jia GF. Reversible RNA modification N1-methyladenosine (m1A) in mRNA and tRNA. Genomics Proteom Bioinf. 2018;16:155–61.CrossRef
9.
go back to reference Chen Z, et al. Transfer RNA demethylase ALKBH3 promotes cancer progression via induction of tRNA-derived small RNAs. Nucleic Acids Res. 2019;47:2533–45.PubMedCrossRef Chen Z, et al. Transfer RNA demethylase ALKBH3 promotes cancer progression via induction of tRNA-derived small RNAs. Nucleic Acids Res. 2019;47:2533–45.PubMedCrossRef
10.
go back to reference Woo HH, Chambers SK. Human ALKBH3-induced m1A demethylation increases the CSF-1 mRNA stability in breast and ovarian cancer cells. BBA-Gene Regul Mech. 2019;1862:35–46. Woo HH, Chambers SK. Human ALKBH3-induced m1A demethylation increases the CSF-1 mRNA stability in breast and ovarian cancer cells. BBA-Gene Regul Mech. 2019;1862:35–46.
11.
go back to reference Wu Y, et al. N1-Methyladenosine (m1A) regulation Associated with the pathogenesis of abdominal aortic aneurysm through YTHDF3 modulating macrophage polarization. Front Cardiovasc Med. 2022;9:883155.PubMedPubMedCentralCrossRef Wu Y, et al. N1-Methyladenosine (m1A) regulation Associated with the pathogenesis of abdominal aortic aneurysm through YTHDF3 modulating macrophage polarization. Front Cardiovasc Med. 2022;9:883155.PubMedPubMedCentralCrossRef
12.
go back to reference Shimada K, et al. ALKBH3 contributes to survival and angiogenesis of human urothelial carcinoma cells through NADPH oxidase and tweak/Fn14/VEGF signals. Clin Cancer Res. 2012;18:5247–55.PubMedCrossRef Shimada K, et al. ALKBH3 contributes to survival and angiogenesis of human urothelial carcinoma cells through NADPH oxidase and tweak/Fn14/VEGF signals. Clin Cancer Res. 2012;18:5247–55.PubMedCrossRef
13.
go back to reference Wang GW, Wang HY, Cheng S, et al. N1-methyladenosine methylation-related metabolic genes signature and subtypes for predicting prognosis and immune microenvironment in osteosarcoma. Front Genet. 2022;13:993594.PubMedPubMedCentralCrossRef Wang GW, Wang HY, Cheng S, et al. N1-methyladenosine methylation-related metabolic genes signature and subtypes for predicting prognosis and immune microenvironment in osteosarcoma. Front Genet. 2022;13:993594.PubMedPubMedCentralCrossRef
14.
go back to reference Gundamaraju R, Lu WY, Paul MK, et al. Autophagy and EMT in cancer and metastasis: who controls whom? BBA -. Mol Basis Disease. 2022;1868(9):166431.CrossRef Gundamaraju R, Lu WY, Paul MK, et al. Autophagy and EMT in cancer and metastasis: who controls whom? BBA -. Mol Basis Disease. 2022;1868(9):166431.CrossRef
16.
go back to reference Rakesh R, PriyaDharshini LC, Sakthivel KM, Rasmi RR. Role and regulation of autophagy in cancer. BBA - Mol Basis Disease. 2022;1868:166400.CrossRef Rakesh R, PriyaDharshini LC, Sakthivel KM, Rasmi RR. Role and regulation of autophagy in cancer. BBA - Mol Basis Disease. 2022;1868:166400.CrossRef
17.
go back to reference Shu F, Xiao H, Li QN, et al. Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets. Signal Transduct Target Ther. 2023;8(1):32.PubMedPubMedCentralCrossRef Shu F, Xiao H, Li QN, et al. Epigenetic and post-translational modifications in autophagy: biological functions and therapeutic targets. Signal Transduct Target Ther. 2023;8(1):32.PubMedPubMedCentralCrossRef
18.
go back to reference Zhang X, et al. Aberrant methylation of ATG2B, ATG4D, ATG9A and ATG9B CpG island promoter is associated with decreased mRNA expression in sporadic breast carcinoma. Gene. 2016;590:285–92.PubMedCrossRef Zhang X, et al. Aberrant methylation of ATG2B, ATG4D, ATG9A and ATG9B CpG island promoter is associated with decreased mRNA expression in sporadic breast carcinoma. Gene. 2016;590:285–92.PubMedCrossRef
19.
go back to reference Liao YP. Hypomethylation signature of tumor-initiating cells predicts poor prognosis of ovarian cancer patients. Hum Mol Genet. 2014;23:1894–906.PubMedCrossRef Liao YP. Hypomethylation signature of tumor-initiating cells predicts poor prognosis of ovarian cancer patients. Hum Mol Genet. 2014;23:1894–906.PubMedCrossRef
20.
go back to reference de Artal-Martinez A, et al. Epigenetic regulation of autophagy by the methyltransferase G9a. Mol Cell Biol. 2013;33:3983–93.CrossRef de Artal-Martinez A, et al. Epigenetic regulation of autophagy by the methyltransferase G9a. Mol Cell Biol. 2013;33:3983–93.CrossRef
21.
go back to reference Hao WC, Dian MJ, Zhou Y, et al. Autophagy induction promoted by m6A reader YTHDF3 through translation upregulation of FOXO3 mRNA. Nat Commun. 2022;13:5845.PubMedPubMedCentralCrossRef Hao WC, Dian MJ, Zhou Y, et al. Autophagy induction promoted by m6A reader YTHDF3 through translation upregulation of FOXO3 mRNA. Nat Commun. 2022;13:5845.PubMedPubMedCentralCrossRef
22.
go back to reference Xu YW, Zhou JC, Li L, et al. FTO-mediated autophagy promotes progression of clear cell renal cell carcinoma via regulating SIK2 mRNA stability. Int J Biol Sci. 2022;18(15):5943–62.PubMedPubMedCentralCrossRef Xu YW, Zhou JC, Li L, et al. FTO-mediated autophagy promotes progression of clear cell renal cell carcinoma via regulating SIK2 mRNA stability. Int J Biol Sci. 2022;18(15):5943–62.PubMedPubMedCentralCrossRef
23.
go back to reference Han H, Zheng SY, Lin SB. N7-methylguanosine (m7G) tRNA modification: a novel autophagy modulator in cancer. Autophagy. 2023;19(1):360–2.PubMedCrossRef Han H, Zheng SY, Lin SB. N7-methylguanosine (m7G) tRNA modification: a novel autophagy modulator in cancer. Autophagy. 2023;19(1):360–2.PubMedCrossRef
25.
go back to reference Liang L, Fang JY, Xu J. Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy. Oncogene. 2016;35:1475–82.PubMedCrossRef Liang L, Fang JY, Xu J. Gastric cancer and gene copy number variation: emerging cancer drivers for targeted therapy. Oncogene. 2016;35:1475–82.PubMedCrossRef
26.
go back to reference Li J, Zuo Z, Lai S, Zheng Z, Liu B, Wei Y, et al. Differential Analysis of RNA methylation regulators in gastric Cancer based on TCGA Data Set and Construction of a Prognostic Model. J Gastrointest Oncol. 2021;12(4):1384–97.PubMedPubMedCentralCrossRef Li J, Zuo Z, Lai S, Zheng Z, Liu B, Wei Y, et al. Differential Analysis of RNA methylation regulators in gastric Cancer based on TCGA Data Set and Construction of a Prognostic Model. J Gastrointest Oncol. 2021;12(4):1384–97.PubMedPubMedCentralCrossRef
27.
go back to reference Wu YM, Chen ZJ, Xie GY, Zhang HS, Wang ZT, Zhou JW, Chen F, Li JX, Chen LK, Niu HN, Wang HS. RNA m1A methylation regulates glycolysis of cancer cells through modulating ATP5D. Proc Natl Acad Sci USA. 2022;119(28):e2119038119.PubMedPubMedCentralCrossRef Wu YM, Chen ZJ, Xie GY, Zhang HS, Wang ZT, Zhou JW, Chen F, Li JX, Chen LK, Niu HN, Wang HS. RNA m1A methylation regulates glycolysis of cancer cells through modulating ATP5D. Proc Natl Acad Sci USA. 2022;119(28):e2119038119.PubMedPubMedCentralCrossRef
28.
go back to reference Mei L, Chen X, Wei F, Huang X, Liu L, Yao J, Chen J, Luo X, Wang Z, Yang A. Tethering ATG16L1 or LC3 induces targeted autophagic degradation of protein aggregates and mitochondria. Autophagy. 2023;13(1):1–17. Mei L, Chen X, Wei F, Huang X, Liu L, Yao J, Chen J, Luo X, Wang Z, Yang A. Tethering ATG16L1 or LC3 induces targeted autophagic degradation of protein aggregates and mitochondria. Autophagy. 2023;13(1):1–17.
29.
30.
go back to reference Li JX, Zhang HS, Wang HS. N1-methyladenosine modification in cancer biology: current status and future perspectives. Comput Struct Biotechnol J. 2022;20:6578–85.PubMedPubMedCentralCrossRef Li JX, Zhang HS, Wang HS. N1-methyladenosine modification in cancer biology: current status and future perspectives. Comput Struct Biotechnol J. 2022;20:6578–85.PubMedPubMedCentralCrossRef
32.
go back to reference Kogaki T, et al. TP53 gene status is a critical determinant of phenotypes induced by ALKBH3 knockdown in non-small cell lung cancers. Biochem Biophys Res Commun. 2017;488:285–90.PubMedCrossRef Kogaki T, et al. TP53 gene status is a critical determinant of phenotypes induced by ALKBH3 knockdown in non-small cell lung cancers. Biochem Biophys Res Commun. 2017;488:285–90.PubMedCrossRef
33.
34.
go back to reference Nakao S, et al. Design and synthesis of prostate cancer antigen-1 (PCA-1/ ALKBH3) inhibitors as anti-prostate cancer drugs. Bioorg Med Chem Lett. 2014;24:1071–4.PubMedCrossRef Nakao S, et al. Design and synthesis of prostate cancer antigen-1 (PCA-1/ ALKBH3) inhibitors as anti-prostate cancer drugs. Bioorg Med Chem Lett. 2014;24:1071–4.PubMedCrossRef
35.
go back to reference Ueda M, et al. Novel metabolically stable PCA-1/ALKBH3 inhibitor has potent Antiproliferative effects on DU145 cells in vivo. Anticancer Res. 2018;38:211–8.PubMed Ueda M, et al. Novel metabolically stable PCA-1/ALKBH3 inhibitor has potent Antiproliferative effects on DU145 cells in vivo. Anticancer Res. 2018;38:211–8.PubMed
36.
37.
go back to reference Fitzmaurice C, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 Cancer groups, 1990 to 2016: a systematic analysis for the global burden of disease study. JAMA Oncol. 2018;4:1553–68.PubMedCrossRef Fitzmaurice C, et al. Global, regional, and national cancer incidence, mortality, years of life lost, years lived with disability, and disability-adjusted life-years for 29 Cancer groups, 1990 to 2016: a systematic analysis for the global burden of disease study. JAMA Oncol. 2018;4:1553–68.PubMedCrossRef
39.
40.
41.
go back to reference Ronot M, Chernyak V, Burgoyne A, et al. Imaging to Predict Prognosis in Hepatocellular Carcinoma: current and future perspectives. Radiology. 2023;307(3):e221429.PubMedCrossRef Ronot M, Chernyak V, Burgoyne A, et al. Imaging to Predict Prognosis in Hepatocellular Carcinoma: current and future perspectives. Radiology. 2023;307(3):e221429.PubMedCrossRef
42.
go back to reference Luo P, Wu S, Yu Y, et al. Current status and perspective biomarkers in AFP negative HCC: towards screening for and diagnosing hepatocellular carcinoma at an earlier stage. Pathol Oncol Res. 2020;26(2):599–603.PubMedCrossRef Luo P, Wu S, Yu Y, et al. Current status and perspective biomarkers in AFP negative HCC: towards screening for and diagnosing hepatocellular carcinoma at an earlier stage. Pathol Oncol Res. 2020;26(2):599–603.PubMedCrossRef
43.
go back to reference Sun M, Taojiao Sun TJ, He ZS, Xiong B. Identification of two novel biomarkers of rectal carcinoma progression and prognosis via co-expression network analysis. Oncotarget. 2017;8(41):69594–609.PubMedPubMedCentralCrossRef Sun M, Taojiao Sun TJ, He ZS, Xiong B. Identification of two novel biomarkers of rectal carcinoma progression and prognosis via co-expression network analysis. Oncotarget. 2017;8(41):69594–609.PubMedPubMedCentralCrossRef
44.
go back to reference Wang XX, Wu LH, Ji HC, et al. A novel cuproptosis-related prognostic signature and potential value in HCC immunotherapy. Front Mol Biosci. 2022;9:1001788.PubMedPubMedCentralCrossRef Wang XX, Wu LH, Ji HC, et al. A novel cuproptosis-related prognostic signature and potential value in HCC immunotherapy. Front Mol Biosci. 2022;9:1001788.PubMedPubMedCentralCrossRef
45.
go back to reference Feng NN, Du XY. Overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma. Front Endocrinol (Lausanne). 2023;13:1061091.PubMedCrossRef Feng NN, Du XY. Overweight/obesity-related transcriptomic signature as a correlate of clinical outcome, immune microenvironment, and treatment response in hepatocellular carcinoma. Front Endocrinol (Lausanne). 2023;13:1061091.PubMedCrossRef
46.
go back to reference Cui YL, Jiang N. Identification of a seven-gene signature predicting clinical outcome of liver cancer based on tumor mutational burden. Hum Cell. 2022;35(4):1192–206.PubMedCrossRef Cui YL, Jiang N. Identification of a seven-gene signature predicting clinical outcome of liver cancer based on tumor mutational burden. Hum Cell. 2022;35(4):1192–206.PubMedCrossRef
47.
go back to reference Qin XN, Chen B. Comprehensive analysis and validation reveal potential MYCN regulatory biomarkers associated with neuroblastoma prognosis. J Biomol Struct Dyn. 2023;41(18):8902–17.PubMedCrossRef Qin XN, Chen B. Comprehensive analysis and validation reveal potential MYCN regulatory biomarkers associated with neuroblastoma prognosis. J Biomol Struct Dyn. 2023;41(18):8902–17.PubMedCrossRef
48.
go back to reference Cai SJ, Du RL, Zhang Y, et al. Construction and Comprehensive Analysis of ceRNA Networks and Tumor-infiltrating Immune cells in Hepatocellular Carcinoma with Vascular Invasion. Front Bioinform. 2022;12:2836981. Cai SJ, Du RL, Zhang Y, et al. Construction and Comprehensive Analysis of ceRNA Networks and Tumor-infiltrating Immune cells in Hepatocellular Carcinoma with Vascular Invasion. Front Bioinform. 2022;12:2836981.
49.
go back to reference Hu GM, Gao F, Wang GZ, et al. Use of proteomics to identify mechanisms of hepatocellular carcinoma with the CYP2D6*10 polymorphism and identification of ANGPTL6 as a new diagnostic and prognostic biomarker. J Transl Med. 2021;19:359.PubMedPubMedCentralCrossRef Hu GM, Gao F, Wang GZ, et al. Use of proteomics to identify mechanisms of hepatocellular carcinoma with the CYP2D6*10 polymorphism and identification of ANGPTL6 as a new diagnostic and prognostic biomarker. J Transl Med. 2021;19:359.PubMedPubMedCentralCrossRef
50.
go back to reference Maimela PWM, Smith M, Nel AJM, et al. Humoral immunoprofiling identifies novel biomarkers and an immune suppressive autoantibody phenotype at the site of disease in pancreatic ductal adenocarcinoma. Front Oncol. 2024;14:1330419.PubMedPubMedCentralCrossRef Maimela PWM, Smith M, Nel AJM, et al. Humoral immunoprofiling identifies novel biomarkers and an immune suppressive autoantibody phenotype at the site of disease in pancreatic ductal adenocarcinoma. Front Oncol. 2024;14:1330419.PubMedPubMedCentralCrossRef
51.
go back to reference Tong Q, Yi MY, Kong PP, et al. TRIM36 inhibits tumorigenesis through the Wnt/β-catenin pathway and promotes caspase-dependent apoptosis in hepatocellular carcinoma. Cancer Cell Int. 2022;22:278.PubMedPubMedCentralCrossRef Tong Q, Yi MY, Kong PP, et al. TRIM36 inhibits tumorigenesis through the Wnt/β-catenin pathway and promotes caspase-dependent apoptosis in hepatocellular carcinoma. Cancer Cell Int. 2022;22:278.PubMedPubMedCentralCrossRef
52.
go back to reference Shi QM, Xue C, Yuan X, He YT, Yu ZJ. Gene signatures and prognostic values of m1Arelated regulatory genes in hepatocellular carcinoma. Sci Rep. 2020;10(1):15083.PubMedPubMedCentralCrossRef Shi QM, Xue C, Yuan X, He YT, Yu ZJ. Gene signatures and prognostic values of m1Arelated regulatory genes in hepatocellular carcinoma. Sci Rep. 2020;10(1):15083.PubMedPubMedCentralCrossRef
53.
go back to reference Corona Velazquez AF, Jackson WT. So many roads: the multifaceted regulation of autophagy induction. Mol Cell Biology. 2018;38:e00303–18.CrossRef Corona Velazquez AF, Jackson WT. So many roads: the multifaceted regulation of autophagy induction. Mol Cell Biology. 2018;38:e00303–18.CrossRef
54.
go back to reference Urra H, Dufey E, Avril T, Chevet E, Hetz C. Endoplasmic reticulum stress and the hallmarks of cancer. Trends Cancer. 2016;2:252–62.PubMedCrossRef Urra H, Dufey E, Avril T, Chevet E, Hetz C. Endoplasmic reticulum stress and the hallmarks of cancer. Trends Cancer. 2016;2:252–62.PubMedCrossRef
Metadata
Title
m1A regulator-mediated methylation modification patterns correlated with autophagy to predict the prognosis of hepatocellular carcinoma
Authors
Yingmin Wu
Lian Li
Long Wang
Shenjie Zhang
Zhirui zeng
Jieyu Lu
Zhi Wang
Yewei Zhang
Shilong Zhang
Haiyang Li
Tengxiang Chen
Publication date
01-12-2024
Publisher
BioMed Central
Published in
BMC Cancer / Issue 1/2024
Electronic ISSN: 1471-2407
DOI
https://doi.org/10.1186/s12885-024-12235-4

Other articles of this Issue 1/2024

BMC Cancer 1/2024 Go to the issue
Webinar | 19-02-2024 | 17:30 (CET)

Keynote webinar | Spotlight on antibody–drug conjugates in cancer

Antibody–drug conjugates (ADCs) are novel agents that have shown promise across multiple tumor types. Explore the current landscape of ADCs in breast and lung cancer with our experts, and gain insights into the mechanism of action, key clinical trials data, existing challenges, and future directions.

Dr. Véronique Diéras
Prof. Fabrice Barlesi
Developed by: Springer Medicine