Promoter Hypermethylation of Neural-related Genes is Compatible with Stemness in Solid Cancers

Overview

Journal Epigenetics Chromatin

Publisher Biomed Central

Specialties Biochemistry
Genetics

Date 2023 Aug 3

PMID 37537688

Authors

Musa Idris

Louis Coussement

Maria M Alves

Tim De Meyer

Veerle Melotte

Affiliations

Soon will be listed here.

Abstract

Background: DNA hypermethylation is an epigenetic feature that modulates gene expression, and its deregulation is observed in cancer. Previously, we identified a neural-related DNA hypermethylation fingerprint in colon cancer, where most of the top hypermethylated and downregulated genes have known functions in the nervous system. To evaluate the presence of this signature and its relevance to carcinogenesis in general, we considered 16 solid cancer types available in The Cancer Genome Atlas (TCGA).

Results: All tested cancers showed significant enrichment for neural-related genes amongst hypermethylated genes. This signature was already present in two premalignant tissue types and could not be explained by potential confounders such as bivalency status or tumor purity. Further characterization of the neural-related DNA hypermethylation signature in colon cancer showed particular enrichment for genes that are overexpressed during neural differentiation. Lastly, an analysis of upstream regulators identified RE1-Silencing Transcription factor (REST) as a potential mediator of this DNA methylation signature.

Conclusion: Our study confirms the presence of a neural-related DNA hypermethylation fingerprint in various cancers, of genes linked to neural differentiation, and points to REST as a possible regulator of this mechanism. We propose that this fingerprint indicates an involvement of DNA hypermethylation in the preservation of neural stemness in cancer cells.

References

Roy N, Hebrok M . Regulation of Cellular Identity in Cancer. Dev Cell. 2015; 35(6):674-84. PMC: 4692359. DOI: 10.1016/j.devcel.2015.12.001. View

Zahalka A, Frenette P . Nerves in cancer. Nat Rev Cancer. 2020; 20(3):143-157. PMC: 7709871. DOI: 10.1038/s41568-019-0237-2. View

Vaes N, Idris M, Boesmans W, Alves M, Melotte V . Nerves in gastrointestinal cancer: from mechanism to modulations. Nat Rev Gastroenterol Hepatol. 2022; 19(12):768-784. DOI: 10.1038/s41575-022-00669-9. View

Hanahan D, Monje M . Cancer hallmarks intersect with neuroscience in the tumor microenvironment. Cancer Cell. 2023; 41(3):573-580. PMC: 10202656. DOI: 10.1016/j.ccell.2023.02.012. View

Zeng Q, Michael I, Zhang P, Saghafinia S, Knott G, Jiao W . Synaptic proximity enables NMDAR signalling to promote brain metastasis. Nature. 2019; 573(7775):526-531. PMC: 6837873. DOI: 10.1038/s41586-019-1576-6. View

Ben Amar D, Thoinet K, Villalard B, Imbaud O, Costechareyre C, Jarrosson L . Environmental cues from neural crest derivatives act as metastatic triggers in an embryonic neuroblastoma model. Nat Commun. 2022; 13(1):2549. PMC: 9091272. DOI: 10.1038/s41467-022-30237-3. View

Lu R, Fan C, Shangguan W, Liu Y, Li Y, Shang Y . Neurons generated from carcinoma stem cells support cancer progression. Signal Transduct Target Ther. 2017; 2:16036. PMC: 5657421. DOI: 10.1038/sigtrans.2016.36. View

Xu L, Zhang M, Shi L, Yang X, Chen L, Cao N . Neural stemness contributes to cell tumorigenicity. Cell Biosci. 2021; 11(1):21. PMC: 7814647. DOI: 10.1186/s13578-021-00531-6. View

Gallik K, Treffy R, Nacke L, Ahsan K, Rocha M, Green-Saxena A . Neural crest and cancer: Divergent travelers on similar paths. Mech Dev. 2017; 148:89-99. PMC: 5811199. DOI: 10.1016/j.mod.2017.08.002. View

10.

Zhang M, Liu Y, Shi L, Fang L, Xu L, Cao Y . Neural stemness unifies cell tumorigenicity and pluripotent differentiation potential. J Biol Chem. 2022; 298(7):102106. PMC: 9254501. DOI: 10.1016/j.jbc.2022.102106. View

11.

Yang X, Cao N, Chen L, Liu L, Zhang M, Cao Y . Suppression of Cell Tumorigenicity by Non-neural Pro-differentiation Factors via Inhibition of Neural Property in Tumorigenic Cells. Front Cell Dev Biol. 2021; 9:714383. PMC: 8476888. DOI: 10.3389/fcell.2021.714383. View

12.

Lei A, Chen L, Zhang M, Yang X, Xu L, Cao N . EZH2 Regulates Protein Stability via Recruiting USP7 to Mediate Neuronal Gene Expression in Cancer Cells. Front Genet. 2019; 10:422. PMC: 6510286. DOI: 10.3389/fgene.2019.00422. View

13.

Jin K, Xiang M . Transcription factor Ptf1a in development, diseases and reprogramming. Cell Mol Life Sci. 2018; 76(5):921-940. PMC: 11105224. DOI: 10.1007/s00018-018-2972-z. View

14.

Kondo T, Sheets P, Zopf D, Aloor H, Cummins T, Chan R . Tlx3 exerts context-dependent transcriptional regulation and promotes neuronal differentiation from embryonic stem cells. Proc Natl Acad Sci U S A. 2008; 105(15):5780-5. PMC: 2311353. DOI: 10.1073/pnas.0708704105. View

15.

Aydin B, Kakumanu A, Rossillo M, Moreno-Estelles M, Garipler G, Ringstad N . Proneural factors Ascl1 and Neurog2 contribute to neuronal subtype identities by establishing distinct chromatin landscapes. Nat Neurosci. 2019; 22(6):897-908. PMC: 6556771. DOI: 10.1038/s41593-019-0399-y. View

16.

Liu X, Campanac E, Cheung H, Ziats M, Canterel-Thouennon L, Raygada M . Idiopathic Autism: Cellular and Molecular Phenotypes in Pluripotent Stem Cell-Derived Neurons. Mol Neurobiol. 2016; 54(6):4507-4523. PMC: 5199629. DOI: 10.1007/s12035-016-9961-8. View

17.

Reyes H, Devor E, Warrier A, Newtson A, Mattson J, Wagner V . Differential DNA methylation in high-grade serous ovarian cancer (HGSOC) is associated with tumor behavior. Sci Rep. 2019; 9(1):17996. PMC: 6884482. DOI: 10.1038/s41598-019-54401-w. View

18.

Fadda A, Gentilini D, Moi L, Barault L, Leoni V, Sulas P . Colorectal cancer early methylation alterations affect the crosstalk between cell and surrounding environment, tracing a biomarker signature specific for this tumor. Int J Cancer. 2018; 143(4):907-920. DOI: 10.1002/ijc.31380. View

19.

Liang Y, Zhang C, Dai D . Identification of differentially expressed genes regulated by methylation in colon cancer based on bioinformatics analysis. World J Gastroenterol. 2019; 25(26):3392-3407. PMC: 6639549. DOI: 10.3748/wjg.v25.i26.3392. View

20.

Yang Y, Chu F, Xu W, Sun J, Sun X, Ma X . Identification of regulatory role of DNA methylation in colon cancer gene expression via systematic bioinformatics analysis. Medicine (Baltimore). 2018; 96(47):e8487. PMC: 5708922. DOI: 10.1097/MD.0000000000008487. View