The DOI matches its Crossref record; 28 of the 28 references it cites were found in a registry or an index.
hTERT Is Expressed in Cancer Cell Lines Despite Promoter DNA Methylation by Preservation of Unmethylated DNA and Active Chromatin around the Transcription Start Site
Published version of a preprint
Abstract
hTERT, which encodes the catalytic subunit of telomerase and is expressed in most immortalized and cancer cells, has been reported to have increased DNA methylation in its promoter region in many cancers. This pattern is inconsistent with observations that DNA methylation of promoter CpG islands is typically associated with gene silencing. Here, we provide a comprehensive analysis of promoter DNA methylation, chromatin patterns, and expression of hTERT in cancer and immortalized cells. Methylation-specific PCR and bisulfite sequencing of the hTERT promoter in breast, lung, and colon cancer cells show that all cancer cell lines retain alleles with little or no methylation around the transcription start site despite being densely methylated in a region 600 bp upstream of the transcription start site. By real-time reverse transcription-PCR, all cancer cell lines express hTERT. Chromatin immunoprecipitation (ChIP) analysis reveals that both active (acetyl-H3K9 and dimethyl-H3K4) and inactive (trimethyl-H3K9 and trimethyl-H3K27) chromatin marks are present across the hTERT promoter. However, using a novel approach combining methylation analysis of ChIP DNA, we show that active chromatin marks are associated with unmethylated DNA, whereas inactive marks of chromatin are associated with methylated DNA in the region around the transcription start site. These results show that DNA methylation patterns of the hTERT promoter (−150 to +150 around the transcription start) are consistent with the usual dynamics of gene expression in that the absence of methylation in this region and the association with active chromatin marks allow for the continued expression of hTERT. [Cancer Res 2007;67(1):194–201]
Overview
Integrity signals
Registry
Cites
Statistics
Verification
Claims the paper makes
Claims other papers make about this one
Each is checked against this paper’s own text: does it say what the citing paper says it does?
In the citing paper
“These data suggest that the absence of methylation and the association with active chromatin marks around the transcription start site allow for the expression of hTERT (Fig. 1), indicating that the DNA methylation pattern of the hTERT promoter is consistent with the usual dynamics of gene expression.”
From Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers (2008) · cites this paper as [62]
Citations
Cites
Jenuwein, T., & Allis, C. D. (2001) · Science · doi:10.1126/science.1063127 · Cited by 9,756
The language of covalent histone modifications
Strahl, B. D., & Allis, C. D. (2000) · Nature · doi:10.1038/47412 · Cited by 8,679
Methylation-specific PCR: a novel PCR assay for methylation status of CpG islands.
Herman, J. G., Graff, J. R., Myöhänen, S., Nelkin, B. D., & Baylin, S. B. (1996) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.93.18.9821 · Cited by 5,634
Self-citationRole of Histone H3 Lysine 27 Methylation in Polycomb-Group Silencing
Cao, R., Wang, L., Wang, H., Xia, L., Erdjument-Bromage, H., Tempst, P., Jones, R. S., & Zhang, Y. (2002) · Science · doi:10.1126/science.1076997 · Cited by 3,775
Gene Silencing in Cancer in Association with Promoter Hypermethylation
Herman, J. G., & Baylin, S. B. (2003) · New England Journal of Medicine · doi:10.1056/nejmra023075 · Cited by 3,471
Self-citationIdentification of a specific telomere terminal transferase activity in tetrahymena extracts
Greider, C. W., & Blackburn, E. H. (1985) · Cell · doi:10.1016/0092-8674(85)90170-9 · Cited by 3,400
The RNA Component of Human Telomerase
Feng, J., Funk, W. D., Wang, S.-S., Weinrich, S. L., Avilion, A. A., Chiu, C.-P., Adams, R. R., Chang, E., Allsopp, R. C., Yu, J., et al. (1995) · Science · doi:10.1126/science.7544491 · Cited by 2,227
Merlo, A., Herman, J. G., Mao, L., Lee, D. J., Gabrielson, E. W., Burger, P. C., Baylin, S. B., & Sidransky, D. (1995) · Nature Medicine · doi:10.1038/nm0795-686 · Cited by 1,992
Self-citationIncidence and functional consequences of hMLH1 promoter hypermethylation in colorectal carcinoma
Herman, J. G., Umar, A., Polyák, K., Graff, J. R., Ahuja, N., Issa, J. J., Markowitz, S. D., Willson, J. K. V., Hamilton, S. R., Kinzler, K. W., et al. (1998) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.95.12.6870 · Cited by 1,887
Self-citationMeyerson, M., Counter, C. M., Eaton, E. N., Ellisen, L. W., Steiner, P., Caddle, S. D., Ziaugra, L., Beijersbergen, R. L., Davidoff, M. J., Liu, Q., et al. (1997) · Cell · doi:10.1016/s0092-8674(00)80538-3 · Cited by 1,784
DNMT1 and DNMT3b cooperate to silence genes in human cancer cells
Rhee, I., Bachman, K. E., Park, B. H., Jair, K.-W., Yen, R.-W. C., Schuebel, K. E., Cui, H., Feinberg, A. P., Lengauer, C., Kinzler, K. W., et al. (2002) · Nature · doi:10.1038/416552a · Cited by 1,039
Self-citationTransitions in Distinct Histone H3 Methylation Patterns at the Heterochromatin Domain Boundaries
Noma, K.-I., Allis, C. D., & Grewal, S. I. S. (2001) · Science · doi:10.1126/science.1064150 · Cited by 764
Integrating the MAP kinase signal into the G1 phase cell cycle machinery
Roovers, K., & Assoian, R. K. (2000) · BioEssays · doi:10.1002/1521-1878(200009)22:9 · Cited by 475
Inhibition of SIRT1 Reactivates Silenced Cancer Genes without Loss of Promoter DNA Hypermethylation
Pruitt, K., Zinn, R. L., Ohm, J. E., McGarvey, K. M., Kang, S.-H. L., Watkins, D. N., Herman, J. G., & Baylin, S. B. (2006) · PLoS Genetics · doi:10.1371/journal.pgen.0020040 · Cited by 387
Self-citationDependence of histone modifications and gene expression on DNA hypermethylation in cancer.
Fahrner, J. A., Eguchi, S., Herman, J. G., & Baylin, S. B. (2002) · PubMed · Cited by 353
Self-citationMcGarvey, K. M., Fahrner, J. A., Greene, E., Martens, J. H. A., Jenuwein, T., & Baylin, S. B. (2006) · Cancer Research · doi:10.1158/0008-5472.can-05-2481 · Cited by 285
Self-citationActivity, function, and gene regulation of the catalytic subunit of telomerase (hTERT)
Poole, J. C., Andrews, L. G., & Tollefsbol, T. O. (2001) · Gene · doi:10.1016/s0378-1119(01)00440-1 · Cited by 280
Hypermethylation can selectively silence individual p16ink4A alleles in neoplasia.
Myöhänen, S., Baylin, S. B., & Herman, J. G. (1998) · PubMed · Cited by 266
Self-citationGuilleret, I., Yan, P., Grange, F., Braunschweig, R., Bosman, F. T., & Benhattar, J. (2002) · International Journal of Cancer · doi:10.1002/ijc.10593 · Cited by 260
Hypermethylation of tumor suppressor genes in cancer
Herman, J. G. (1999) · Seminars in Cancer Biology · doi:10.1006/scbi.1999.0138 · Cited by 225
Self-citationFaiola, F., Liu, X., Lo, S.-Y., Pan, S., Zhang, K., Lymar, E. S., Farina, A. N., & Martinez, E. (2005) · Molecular and Cellular Biology · doi:10.1128/mcb.25.23.10220-10234.2005 · Cited by 220
Devereux, T. R., Horikawa, I., Anna, C. H., Annab, L. A., Afshari, C. A., & Barrett, J. C. (1999) · PubMed · Cited by 215
Methylation of the human telomerase gene CpG island.
Dessain, S. K., Yu, H., Reddel, R. R., Beijersbergen, R. L., & Weinberg, R. A. (2000) · PubMed · Cited by 185
Lopatina, N., Poole, J. C., Saldanha, S. N., Hansen, N. J., Key, J. S., Pita, M. A., Andrews, L. G., & Tollefsbol, T. O. (2003) · Biochemical and Biophysical Research Communications · doi:10.1016/s0006-291x(03)01033-7 · Cited by 82
Unusual distribution of DNA methylation within the hTERT CpG island in tissues and cell lines
Guilleret, I., & Benhattar, J. (2004) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2004.10.137 · Cited by 81
Shin, K.-H., Kang, M., Dicterow, E., & Park, N.-H. (2003) · British Journal of Cancer · doi:10.1038/sj.bjc.6601291 · Cited by 74
Liu, L., Saldanha, S. N., Pate, M. S., Andrews, L. G., & Tollefsbol, T. O. (2004) · Genes Chromosomes and Cancer · doi:10.1002/gcc.20058 · Cited by 67
Nomoto, K. (2002) · Japanese Journal of Clinical Oncology · doi:10.1093/jjco/hyf001 · Cited by 51
Cited by
Sorted by citations
Integrating oncolytic viruses in combination cancer immunotherapy
Bommareddy, P. K., Shettigar, M., & Kaufman, H. L. (2018) · Nature reviews. Immunology · doi:10.1038/s41577-018-0014-6 · Cited by 704
Lim, S., Gu, J.-M., Kim, M. S., Kim, H. S., Park, Y. N., Park, C. K., Cho, J. W., Park, Y. M., & Jung, G. (2008) · Gastroenterology · doi:10.1053/j.gastro.2008.07.027 · Cited by 386
Sulforaphane Causes Epigenetic Repression of hTERT Expression in Human Breast Cancer Cell Lines
Meeran, S. M., Patel, S. N., & Tollefsbol, T. O. (2010) · PLoS ONE · doi:10.1371/journal.pone.0011457 · Cited by 372
Understanding and exploiting hTERT promoter regulation for diagnosis and treatment of human cancers
Kyo, S., Takakura, M., Fujiwara, T., & Inoue, M. (2008) · Cancer Science · doi:10.1111/j.1349-7006.2008.00878.x · Cited by 347
TERT—Regulation and Roles in Cancer Formation
Dratwa, M., Wysoczańska, B., Łacina, P., Kubik, T., & Bogunia‐Kubik, K. (2020) · Frontiers in Immunology · doi:10.3389/fimmu.2020.589929 · Cited by 331
Metadata
- Authors
- Zinn, R. L., Pruitt, K., Eguchi, S., Baylin, S. B., & Herman, J. G.
- Affiliations
- Johns Hopkins University (US)
- Venue
- Cancer Research
- Published
- 2007-01-01
- Volume
- 67
- Issue
- 1
- Pages
- 194-201
- ISSN
- 0008-5472 (ISSN-L)
- 1538-7445
- OpenAlex
- W2069698023
- Cited by
- 210
- References
- 28
- Citations by year
- 2026: 2 · 2025: 3 · 2024: 5 · 2023: 11 · 2022: 9 · 2021: 6 · 2020: 13 · 2019: 15 · 2018: 11 · 2017: 9 · 2016: 16 · 2015: 15 · 2014: 11 · 2013: 9 · 2012: 12
- FWCI
- 6.23
- Type
- journal article
- Language
- en
- Open access
- closed
- Locations
- Cancer Research (publishedVersion)
- PubMed (publishedVersion)
- Funders
- National Cancer Institute (CA088843, P50CA088843)
- National Institute of Environmental Health Sciences (R01ES011858, ES 11858)
- Topics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Epigenetics and DNA Methylation
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Cell Biology › Telomeres, Telomerase, and Senescence
- Keywords
- hTERT, telomerase reverse transcriptase, promoter methylation, transcription start sites, gene expression, cancer cell lines, CpG islands, histone modifications, H3K9 acetylation, H3K4 dimethylation, H3K9 trimethylation, H3K27me3, gene silencing, breast cancer, lung cancer, colon cancer
- MeSH terms
- Alleles, Breast Neoplasms, Chromatin, Colonic Neoplasms, Humans, Leukemia, Lung Neoplasms, Neoplasms, Promoter Regions, Genetic, Gene Expression, Caco-2 Cells, Telomerase, DNA Methylation, Transcription Initiation Site, HCT116 Cells, Cell Line, Tumor
About these checks
Registry, retraction, Cites and statistics results are computed, not judged, with one exception: a printed reference that no index lists is read once by a model before it counts as a citation error. Claims are extracted by a model and kept only when their quote appears verbatim in the text; each cited source is then checked, with a model’s help, for whether it says what the claim relies on. Those verdicts can be wrong — read the claim’s quote and the cited source before relying on one.
Statistics and arithmetic are recomputed, not judged.
Confidence bands are shown only for fields calibrated on our annotated test set. None is calibrated yet, so no band is shown.
What counts as a claim ›How we measure confidence ›How we check this ›
Are you an author, or do you see a problem with this page? Request a review
