Global Promoter Methylation Analysis Reveals Novel Candidate Tumor Suppressor Genes in Natural Killer Cell Lymphoma Article Swipe
Can Küçük
,
Xiaozhou Hu
,
Bei Jiang
,
David Klinkebiel
,
Huimin Geng
,
Qiang Gong
,
Alyssa Bouska
,
Javeed Iqbal
,
Philippe Gaulard
,
Timothy W. McKeithan
,
Wing C. Chan
·
YOU?
·
· 2015
· Open Access
·
· DOI: https://doi.org/10.1158/1078-0432.ccr-14-1216
YOU?
·
· 2015
· Open Access
·
· DOI: https://doi.org/10.1158/1078-0432.ccr-14-1216
Purpose: To identify tumor suppressor genes epigenetically silenced by promoter hypermethylation in extranodal natural killer cell lymphoma (NKCL). Experimental Design: Promoter methylation was analyzed with global and locus-specific methylation assays in NKCL cases and NK cell lines. Gene expression profiles were used to identify genes for which aberrant promoter methylation was associated with transcriptional silencing. Selected DNA methylations were validated by RRBS, pyrosequencing, or q-MSP. Decitabine treatment was performed to evaluate reactivation of methylated genes. The tumor suppressor effect of silenced genes was evaluated functionally by reintroducing them into NK cell lines. Results: We observed significant promoter hypermethylation in most NKCL samples compared with normal NK cells. Correlation of global promoter methylation with gene expression profiles identified 95 genes with strong evidence for being silenced because of promoter methylation, including BCL2L11 (BIM), DAPK1, PTPN6 (SHP1), TET2, SOCS6, and ASNS. Known tumor suppressor genes were significantly overrepresented in this set of genes. Decitabine treatment of NK cell lines was associated with reexpression of all 10 selected methylated and silenced genes. Ectopic expression of frequently silenced BIM in two BIM-nonexpressing NK cell lines led to increased apoptosis and eventual elimination of BIM-transduced cells. It also sensitized these cell lines to chemotherapy-induced apoptosis. Similarly, reintroduction of SOCS6 significantly inhibited growth in SOCS6-nonexpressing NK cell lines. NK cell lines lacking ASNS expression showed increased sensitivity to treatment with l-asparaginase. Reintroduction of ASNS reduced drug sensitivity. Conclusion: Promoter region hypermethylation is frequent in NKCL, and aberrantly methylated genes are pathologically and clinically significant. Clin Cancer Res; 21(7); 1699–711. ©2015 AACR.
Related Topics
Concepts
Suppressor
Methylation
Lymphoma
Gene
Biology
DNA methylation
Cancer research
Tumor suppressor gene
Natural killer cell
Promoter
Genetics
Immunology
Carcinogenesis
Gene expression
Cytotoxicity
In vitro
Metadata
- Type
- article
- Language
- en
- Landing Page
- https://doi.org/10.1158/1078-0432.ccr-14-1216
- https://clincancerres.aacrjournals.org/content/clincanres/21/7/1699.full.pdf
- OA Status
- bronze
- Cited By
- 102
- References
- 46
- Related Works
- 10
- OpenAlex ID
- https://openalex.org/W2167621352
All OpenAlex metadata
Raw OpenAlex JSON
- OpenAlex ID
-
https://openalex.org/W2167621352Canonical identifier for this work in OpenAlex
- DOI
-
https://doi.org/10.1158/1078-0432.ccr-14-1216Digital Object Identifier
- Title
-
Global Promoter Methylation Analysis Reveals Novel Candidate Tumor Suppressor Genes in Natural Killer Cell LymphomaWork title
- Type
-
articleOpenAlex work type
- Language
-
enPrimary language
- Publication year
-
2015Year of publication
- Publication date
-
2015-01-23Full publication date if available
- Authors
-
Can Küçük, Xiaozhou Hu, Bei Jiang, David Klinkebiel, Huimin Geng, Qiang Gong, Alyssa Bouska, Javeed Iqbal, Philippe Gaulard, Timothy W. McKeithan, Wing C. ChanList of authors in order
- Landing page
-
https://doi.org/10.1158/1078-0432.ccr-14-1216Publisher landing page
- PDF URL
-
https://clincancerres.aacrjournals.org/content/clincanres/21/7/1699.full.pdfDirect link to full text PDF
- Open access
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YesWhether a free full text is available
- OA status
-
bronzeOpen access status per OpenAlex
- OA URL
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https://clincancerres.aacrjournals.org/content/clincanres/21/7/1699.full.pdfDirect OA link when available
- Concepts
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Suppressor, Methylation, Lymphoma, Gene, Biology, DNA methylation, Cancer research, Tumor suppressor gene, Natural killer cell, Promoter, Genetics, Immunology, Carcinogenesis, Gene expression, Cytotoxicity, In vitroTop concepts (fields/topics) attached by OpenAlex
- Cited by
-
102Total citation count in OpenAlex
- Citations by year (recent)
-
2025: 7, 2024: 20, 2023: 12, 2022: 10, 2021: 6Per-year citation counts (last 5 years)
- References (count)
-
46Number of works referenced by this work
- Related works (count)
-
10Other works algorithmically related by OpenAlex
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| abstract_inverted_index.sensitized | 194 |
| abstract_inverted_index.silencing. | 55 |
| abstract_inverted_index.suppressor | 5, 78, 142 |
| abstract_inverted_index.1699–711. | 253 |
| abstract_inverted_index.Conclusion: | 232 |
| abstract_inverted_index.Correlation | 108 |
| abstract_inverted_index.elimination | 188 |
| abstract_inverted_index.methylation | 22, 29, 50, 112 |
| abstract_inverted_index.sensitivity | 221 |
| abstract_inverted_index.significant | 96 |
| abstract_inverted_index.Experimental | 19 |
| abstract_inverted_index.functionally | 85 |
| abstract_inverted_index.methylation, | 129 |
| abstract_inverted_index.methylations | 58 |
| abstract_inverted_index.reactivation | 72 |
| abstract_inverted_index.reexpression | 161 |
| abstract_inverted_index.sensitivity. | 231 |
| abstract_inverted_index.significant. | 248 |
| abstract_inverted_index.reintroducing | 87 |
| abstract_inverted_index.significantly | 145, 205 |
| abstract_inverted_index.BIM-transduced | 190 |
| abstract_inverted_index.Reintroduction | 226 |
| abstract_inverted_index.epigenetically | 7 |
| abstract_inverted_index.locus-specific | 28 |
| abstract_inverted_index.pathologically | 245 |
| abstract_inverted_index.reintroduction | 202 |
| abstract_inverted_index.l-asparaginase. | 225 |
| abstract_inverted_index.overrepresented | 146 |
| abstract_inverted_index.pyrosequencing, | 63 |
| abstract_inverted_index.transcriptional | 54 |
| abstract_inverted_index.hypermethylation | 11, 98, 235 |
| abstract_inverted_index.BIM-nonexpressing | 178 |
| abstract_inverted_index.SOCS6-nonexpressing | 209 |
| abstract_inverted_index.chemotherapy-induced | 199 |
| cited_by_percentile_year.max | 100 |
| cited_by_percentile_year.min | 98 |
| corresponding_author_ids | https://openalex.org/A5015247283 |
| countries_distinct_count | 3 |
| institutions_distinct_count | 11 |
| corresponding_institution_ids | https://openalex.org/I1301076528 |
| sustainable_development_goals[0].id | https://metadata.un.org/sdg/3 |
| sustainable_development_goals[0].score | 0.800000011920929 |
| sustainable_development_goals[0].display_name | Good health and well-being |
| citation_normalized_percentile.value | 0.95457435 |
| citation_normalized_percentile.is_in_top_1_percent | False |
| citation_normalized_percentile.is_in_top_10_percent | True |