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Review
. 2023 May;1878(3):188901.
doi: 10.1016/j.bbcan.2023.188901. Epub 2023 Apr 28.

Epigenetic regulation of cancer-associated fibroblast heterogeneity

Rachel J Kehrberg  1 , Namita Bhyravbhatla  1 , Surinder K Batra  2 , Sushil Kumar  3
Affiliations
Review

Epigenetic regulation of cancer-associated fibroblast heterogeneity

Rachel J Kehrberg et al. Biochim Biophys Acta Rev Cancer. 2023 May.

Abstract

Cancer-associated fibroblasts (CAFs), a significant component of the tumor microenvironment (TME), contribute to cancer progression through the secretion of extracellular matrix (ECM), growth factors, and metabolites. It is now well recognized that CAFs are a heterogenous population with ablation experiments leading to reduced tumor growth and single-cell RNA sequencing demonstrating CAF subgroups. CAFs lack genetic mutations yet substantially differ from their normal stromal precursors. Here, we review epigenetic changes in CAF maturation, focusing on DNA methylation and histone modifications. DNA methylation changes in CAFs have been demonstrated globally, while roles of methylation at specific genes affect tumor growth. Further, loss of CAF histone methylation and gain of histone acetylation has been shown to promote CAF activation and tumor promotion. Many CAF activating factors, such as transforming growth factor β (TGFβ), lead to these epigenetic changes. MicroRNAs (miRNAs) serve as targets and orchestrators of epigenetic modifications that influence gene expression. Bromodomain and extra-terminal domain (BET), an epigenetic reader, recognizes histone acetylation and activates the transcription of genes leading to the pro-tumor phenotype of CAFs.

Keywords: Cancer-associated fibroblasts; DNA methylation; Epigenetics; Histone acetylation; Histone methylation; Tumor microenvironment.

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Conflict of interest statement

Declaration of Competing Interest S.K.B. is a founder of Sanguine Diagnostics and Therapeutics, Inc. Other authors have no competing interests to declare.

Figures

Figure 1.
Figure 1.. DNA methylation changes during CAF maturation.
CAFs undergo both DNA hypermethylation and hypomethylation, leading to increases and decrease in signaling pathways causing CAF activation.
Figure 2.
Figure 2.. Epigenetic writers, erasers, and readers that promote or inhibit CAF maturation.
Epigenetic enzymes add, remove, or interact with histone PTMs and DNA methylation. Inhibiting these enzymes can have positive or negative effects on CAF function.
Figure 3.
Figure 3.. Common CAF subtypes are derived from various CAF precursors after exposure to CAF activating factors.
Factors secreted by cancer cells and other TME cells cause CAF precursors to mature into CAFs through epigenetic mechanisms.
See this image and copyright information in PMC

References

    1. Sahai E, Astsaturov I, Cukierman E, DeNardo DG, Egeblad M, Evans RM, Fearon D, Greten FR, Hingorani SR, Hunter T, et al. (2020). A framework for advancing our understanding of cancer-associated fibroblasts. Nat Rev Cancer 20, 174–186. 10.1038/s41568-019-0238-1. - DOI - PMC - PubMed
    1. Santi A, Kugeratski FG, and Zanivan S (2018). Cancer Associated Fibroblasts: The Architects of Stroma Remodeling. Proteomics 18, e1700167. 10.1002/pmic.201700167. - DOI - PMC - PubMed
    1. Chen Y, McAndrews KM, and Kalluri R (2021). Clinical and therapeutic relevance of cancer-associated fibroblasts. Nat Rev Clin Oncol 18, 792–804. 10.1038/s41571-021-00546-5. - DOI - PMC - PubMed
    1. Harper J, and Sainson RC (2014). Regulation of the anti-tumour immune response by cancer-associated fibroblasts. Semin Cancer Biol 25, 69–77.10.1016/j.semcancer.2013.12.005. - DOI - PubMed
    1. Zheng S, Liang JY, Tang Y, Xie J, Zou Y, Yang A, Shao N, Kuang X, Ji F, Liu X, et al. (2023). Dissecting the role of cancer-associated fibroblast-derived biglycan as a potential therapeutic target in immunotherapy resistance: A tumor bulk and single-cell transcriptomic study. Clin Transl Med 13, e1189. 10.1002/ctm2.1189. - DOI - PMC - PubMed

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