Lineage-specific RUNX3 hypomethylation marks the preneoplastic immune component of gastric cancer
Runt domain transcription factor 3 (RUNX3) is widely regarded as a tumour-suppressor gene inactivated by DNA hypermethylation of its canonical CpG (cytidine-phosphate-guanidine) island (CGI) promoter in gastric cancer (GC). Absence of RUNX3 expression from normal gastric epithelial cells (GECs), the...
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| Format: | Article |
| Language: | en_US |
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Nature Publishing Group
2017
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| Online Access: | http://hdl.handle.net/1721.1/108192 https://orcid.org/0000-0001-9307-6116 |
| _version_ | 1826195750741082112 |
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| author | Kurklu, B Whitehead, R H Ong, E K Minamoto, T Mann, J R Judd, L M Giraud, A S Menheniott, T R Fox, James G |
| author2 | Massachusetts Institute of Technology. Department of Biological Engineering |
| author_facet | Massachusetts Institute of Technology. Department of Biological Engineering Kurklu, B Whitehead, R H Ong, E K Minamoto, T Mann, J R Judd, L M Giraud, A S Menheniott, T R Fox, James G |
| author_sort | Kurklu, B |
| collection | MIT |
| description | Runt domain transcription factor 3 (RUNX3) is widely regarded as a tumour-suppressor gene inactivated by DNA hypermethylation of its canonical CpG (cytidine-phosphate-guanidine) island (CGI) promoter in gastric cancer (GC). Absence of RUNX3 expression from normal gastric epithelial cells (GECs), the progenitors to GC, coupled with frequent RUNX3 overexpression in GC progression, challenge this longstanding paradigm. However, epigenetic models to better describe RUNX3 deregulation in GC have not emerged. Here, we identify lineage-specific DNA methylation at an alternate, non-CGI promoter (P1) as a new mechanism of RUNX3 epigenetic control. In normal GECs, P1 was hypermethylated and repressed, whereas in immune lineages P1 was hypomethylated and widely expressed. In human GC development, we detected aberrant P1 hypomethylation signatures associated with the early inflammatory, preneoplastic and tumour stages. Aberrant P1 hypomethylation was fully recapitulated in mouse models of gastric inflammation and tumorigenesis. Cell sorting showed that P1 hypomethylation reflects altered cell-type composition of the gastric epithelium/tumour microenvironment caused by immune cell recruitment, not methylation loss. Finally, via long-term culture of gastric tumour epithelium, we revealed that de novo methylation of the RUNX3 canonical CGI promoter is a bystander effect of oncogenic immortalization and not likely causal in GC pathogenesis as previously argued. We propose a new model of RUNX3 epigenetic control in cancer, based on immune-specific, non-CGI promoter hypomethylation. This novel epigenetic signature may have utility in early detection of GC and possibly other epithelial cancers with premalignant immune involvement. |
| first_indexed | 2024-09-23T10:14:51Z |
| format | Article |
| id | mit-1721.1/108192 |
| institution | Massachusetts Institute of Technology |
| language | en_US |
| last_indexed | 2024-09-23T10:14:51Z |
| publishDate | 2017 |
| publisher | Nature Publishing Group |
| record_format | dspace |
| spelling | mit-1721.1/1081922022-09-30T19:54:35Z Lineage-specific RUNX3 hypomethylation marks the preneoplastic immune component of gastric cancer Kurklu, B Whitehead, R H Ong, E K Minamoto, T Mann, J R Judd, L M Giraud, A S Menheniott, T R Fox, James G Massachusetts Institute of Technology. Department of Biological Engineering Massachusetts Institute of Technology. Division of Comparative Medicine Fox, James G Runt domain transcription factor 3 (RUNX3) is widely regarded as a tumour-suppressor gene inactivated by DNA hypermethylation of its canonical CpG (cytidine-phosphate-guanidine) island (CGI) promoter in gastric cancer (GC). Absence of RUNX3 expression from normal gastric epithelial cells (GECs), the progenitors to GC, coupled with frequent RUNX3 overexpression in GC progression, challenge this longstanding paradigm. However, epigenetic models to better describe RUNX3 deregulation in GC have not emerged. Here, we identify lineage-specific DNA methylation at an alternate, non-CGI promoter (P1) as a new mechanism of RUNX3 epigenetic control. In normal GECs, P1 was hypermethylated and repressed, whereas in immune lineages P1 was hypomethylated and widely expressed. In human GC development, we detected aberrant P1 hypomethylation signatures associated with the early inflammatory, preneoplastic and tumour stages. Aberrant P1 hypomethylation was fully recapitulated in mouse models of gastric inflammation and tumorigenesis. Cell sorting showed that P1 hypomethylation reflects altered cell-type composition of the gastric epithelium/tumour microenvironment caused by immune cell recruitment, not methylation loss. Finally, via long-term culture of gastric tumour epithelium, we revealed that de novo methylation of the RUNX3 canonical CGI promoter is a bystander effect of oncogenic immortalization and not likely causal in GC pathogenesis as previously argued. We propose a new model of RUNX3 epigenetic control in cancer, based on immune-specific, non-CGI promoter hypomethylation. This novel epigenetic signature may have utility in early detection of GC and possibly other epithelial cancers with premalignant immune involvement. 2017-04-14T20:42:10Z 2017-04-14T20:42:10Z 2014-08 2014-06 Article http://purl.org/eprint/type/JournalArticle 0950-9232 1476-5594 http://hdl.handle.net/1721.1/108192 Kurklu, B et al. “Lineage-Specific RUNX3 Hypomethylation Marks the Preneoplastic Immune Component of Gastric Cancer.” Oncogene 34.22 (2015): 2856–2866. https://orcid.org/0000-0001-9307-6116 en_US http://dx.doi.org/10.1038/onc.2014.233 Oncogene Creative Commons Attribution-Noncommercial-Share Alike http://creativecommons.org/licenses/by-nc-sa/4.0/ application/pdf Nature Publishing Group PMC |
| spellingShingle | Kurklu, B Whitehead, R H Ong, E K Minamoto, T Mann, J R Judd, L M Giraud, A S Menheniott, T R Fox, James G Lineage-specific RUNX3 hypomethylation marks the preneoplastic immune component of gastric cancer |
| title | Lineage-specific RUNX3 hypomethylation marks the preneoplastic immune component of gastric cancer |
| title_full | Lineage-specific RUNX3 hypomethylation marks the preneoplastic immune component of gastric cancer |
| title_fullStr | Lineage-specific RUNX3 hypomethylation marks the preneoplastic immune component of gastric cancer |
| title_full_unstemmed | Lineage-specific RUNX3 hypomethylation marks the preneoplastic immune component of gastric cancer |
| title_short | Lineage-specific RUNX3 hypomethylation marks the preneoplastic immune component of gastric cancer |
| title_sort | lineage specific runx3 hypomethylation marks the preneoplastic immune component of gastric cancer |
| url | http://hdl.handle.net/1721.1/108192 https://orcid.org/0000-0001-9307-6116 |
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