Transcriptomic profiling disclosed the role of DNA methylation and histone modifications in tumor-infiltrating myeloid-derived suppressor cell subsets in colorectal cancer

Sasidharan Nair, V, Saleh, R, Toor, SM, Taha, RZ, Ahmed, AA, Kurer, MA, Murshed, K, Alajez, NM, Abu Nada, M and Elkord, E ORCID: https://orcid.org/0000-0002-3868-0318 2020, 'Transcriptomic profiling disclosed the role of DNA methylation and histone modifications in tumor-infiltrating myeloid-derived suppressor cell subsets in colorectal cancer' , Clinical Epigenetics, 12 (1) , p. 13.

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Abstract

Increased numbers of myeloid-derived suppressor cells (MDSCs) are positively correlated with poor prognosis and reduced survivals of cancer patients. They play central roles in tumor immune evasion and tumor metastasis. However, limited data are available on phenotypic/transcriptomic characteristics of the different MDSCs subsets in cancer. These cells include immature (I-MDSCs), monocytic (M-MDSCs), and polymorphonuclear/granulocytic (PMN-MDSCs). Phenotypic characterization of myeloid subsets from 27 colorectal cancer (CRC) patients was assessed by flow cytometric analyses. RNA-sequencing of sorted I-MDSCs, PMN-MDSCs, and antigen-presenting cells (APCs) was also performed. We found that the levels of I-MDSCs and PMN-MDSCs were increased in tumor tissues (TT), compared with normal tissues (NT) in colorectal cancer. Our functional annotation analyses showed that genes associated with histone deacetylase (HDAC) activation- and DNA methylation-mediated transcriptional silencing were upregulated, and histone acetyl transferase (HAT)-related genes were downregulated in tumor-infiltrating I-MDSCs. Moreover, pathways implicated in cell trafficking and immune suppression, including Wnt, interleukin-6 (IL-6), and mitogen-activated protein kinase (MAPK) signaling, were upregulated in I-MDSCs. Notably, PMN-MDSCs showed downregulation in genes related to DNA methylation and HDAC binding. Using an ex vivo model, we found that inhibition of HDAC activation or neutralization of IL-6 in CRC tumor tissues downregulates the expression of genes associated with immunosuppression and myeloid cell chemotaxis, confirming the importance of HDAC activation and IL-6 signaling pathway in MDSC function and chemotaxis. This study provides novel insights into the epigenetic regulations and other molecular pathways in different myeloid cell subsets within the CRC tumor microenvironment (TME), giving opportunities to potential targets for therapeutic benefits.

Item Type: Article
Additional Information: ** From PubMed via Jisc Publications Router **Journal IDs: eissn 1868-7083 **Article IDs: pubmed: 31941522; pii: 10.1186/s13148-020-0808-9; pmc: PMC6964037 **History: accepted 03-01-2020; submitted 12-10-2019
Uncontrolled Keywords: Colorectal cancer, DNA methylation, Histone modifications, Myeloid-derived suppressor cells, Transcriptomic profile
Schools: Schools > School of Environment and Life Sciences > Biomedical Research Centre
Journal or Publication Title: Clinical Epigenetics
Publisher: Springer
ISSN: 1868-7075
Related URLs:
Funders: Qatar Foundation
SWORD Depositor: Publications Router
Depositing User: Publications Router
Date Deposited: 30 Jan 2020 09:20
Last Modified: 30 Jan 2020 09:30
URI: http://usir.salford.ac.uk/id/eprint/56329

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