The DOI matches its Crossref record; 11 of the 11 references it cites were found in a registry or an index.
Methylation of the KEAP1 gene promoter region in human colorectal cancer
Open accessAbstract
Background: The Keap1-Nrf2 pathway has been reported to be impaired in several cancers. However, the status of Keap1-Nrf2 system in human colorectal cancer (CRC) has not been elucidated. Methods: We used colorectal cancer (CRC) cell lines and surgical specimens to investigate the methylation status of the KEAP1 promoter region as well as expression of Nrf2 and its downstream antioxidative stress genes, NQO-1 and AKR1C1. Results: DNA sequencing analysis indicated that all mutations detected were synonymous, with no amino acid substitutions. We showed by bisulfite genomic sequencing and methylation-specific PCR that eight of 10 CRC cell lines had hypermethylated CpG islands in the KEAP1 promoter region. HT29 cells with a hypermethylated KEAP1 promoter resulted in decreased mRNA and protein expression but unmethylated Colo320DM cells showed higher expression levels. In addition, treatment with the DNA methyltransferase inhibitor 5-Aza-dC combined with the histone deacetylase inhibitor trichostatin A (TSA) increased KEAP1 mRNA expression. These result suggested that methylation of the KEAP1 promoter regulates its mRNA level. Time course analysis with the Nrf2-antioxidant response element (ARE) pathway activator t-BHQ treatment showed a rapid response within 24 h. HT29 cells had higher basal expression levels of NQO-1 and AKR1C1 mRNA than Colo320DM cells. Aberrant promoter methylation of KEAP1 was detected in 53% of tumor tissues and 25% of normal mucosae from 40 surgical CRC specimens, indicating that cancerous tissue showed increased methylation of the KEAP1 promoter region, conferring a protective effect against cytotoxic anticancer drugs. Conclusion: Hypermethylation of the KEAP1 promoter region suppressed its mRNA expression and increased nuclear Nrf2 and downstream ARE gene expression in CRC cells and tissues.
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Self-citationDinkova-Kostova, A. T., Holtzclaw, W. D., Cole, R. N., Itoh, K., Wakabayashi, N., Katoh, Y., Yamamoto, M., & Talalay, P. (2002) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.172398899 · Cited by 1,947
Self-citationMoi, P., Chan, K., Asunis, I., Cao, A., & Kan, Y. W. (1994) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.91.21.9926 · Cited by 1,607
Dysfunctional KEAP1–NRF2 Interaction in Non-Small-Cell Lung Cancer
Singh, A., Misra, V., Thimmulappa, R. K., Lee, H., Ames, S., Hoque, M. O., Herman, J. G., Baylin, S. B., Sidransky, D., Gabrielson, E., et al. (2006) · PLoS Medicine · doi:10.1371/journal.pmed.0030420 · Cited by 1,060
Wakabayashi, N., Dinkova-Kostova, A. T., Holtzclaw, W. D., Kang, M.-I., Kobayashi, A., Yamamoto, M., Kensler, T. W., & Talalay, P. (2004) · Proceedings of the National Academy of Sciences · doi:10.1073/pnas.0307301101 · Cited by 986 · cited 1×
“Under physiological conditions, Keap1 maintains a low basal level of Nrf2 by constantly targeting Nrf2 for ubiquitin-mediated protein degradation [13,14].”
BackgroundStructural basis for defects of Keap1 activity provoked by its point mutations in lung cancer
Padmanabhan, B., Tong, K. I., Ohta, T., Nakamura, Y., Scharlock, M., Ohtsuji, M., Kang, M.-I., Kobayashi, A., Yokoyama, S., & Yamamoto, M. (2006) · Molecular Cell · doi:10.1016/j.molcel.2006.01.013 · Cited by 735 · cited 1×
“The Keap1-Nrf2 signaling pathway is impaired in lung cancer, which is caused by mutations within functionally important domains of the KEAP1 or NRF2 gene [15-17].”
BackgroundHigh Levels of Nrf2 Determine Chemoresistance in Type II Endometrial Cancer
Jiang, T., Chen, N., Zhao, F., Wang, X.-J., Kong, B., Zheng, W., & Zhang, D. D. (2010) · Cancer Research · doi:10.1158/0008-5472.can-10-0713 · Cited by 286
A mutation of Keap1 found in breast cancer impairs its ability to repress Nrf2 activity
Nioi, P., & Nguyen, T. (2007) · Biochemical and Biophysical Research Communications · doi:10.1016/j.bbrc.2007.08.051 · Cited by 212
Cited by
The Molecular Mechanisms Regulating the KEAP1-NRF2 Pathway
Baird, L., & Yamamoto, M. (2020) · Molecular and Cellular Biology · doi:10.1128/mcb.00099-20 · Cited by 1,542
The Keap1-Nrf2 pathway: Mechanisms of activation and dysregulation in cancer
Kansanen, E., Kuosmanen, S. M., Leinonen, H., & Levonen, A.-L. (2013) · Redox Biology · doi:10.1016/j.redox.2012.10.001 · Cited by 1,313
“(B) Hypermethylation of the Keap1 promoter in lung and prostate cancer leads to reduction of Keap1 mRNA expression, which increases the nuclear accumulation of Nrf2 [6,7].”
BackgroundKeap1 loss promotes Kras-driven lung cancer and results in dependence on glutaminolysis
Romero, R., Sayin, V. I., Davidson, S. M., Bauer, M. R., Singh, S. X., LeBoeuf, S. E., Karakousi, T. R., Ellis, D. C., Bhutkar, A., Sánchez-Rivera, F. J., et al. (2017) · Nature Medicine · doi:10.1038/nm.4407 · Cited by 652
The Dual Roles of NRF2 in Cancer
Menegon, S., Columbano, A., & Giordano, S. (2016) · Trends in Molecular Medicine · doi:10.1016/j.molmed.2016.05.002 · Cited by 633
Nrf2 Activation Promotes Lung Cancer Metastasis by Inhibiting the Degradation of Bach1
Lignitto, L., LeBoeuf, S. E., Homer, H., Jiang, S., Askenazi, M., Karakousi, T. R., Pass, H. I., Bhutkar, A. J., Tsirigos, A., Ueberheide, B., et al. (2019) · Cell · doi:10.1016/j.cell.2019.06.003 · Cited by 573
Metadata
- Authors
- Hanada, N., Takahata, T., Zhou, Q., Ye, X., Sun, R., Itoh, J., Ishiguro, A., Kijima, H., Mimura, J., Itoh, K., Fukuda, S., & Saijo, Y.
- Venue
- BMC Cancer
- Published
- 2012-02-13
- Volume
- 12
- Issue
- 1
- Pages
- 66-66
- ISSN
- 1471-2407 (ISSN-L)
- OpenAlex
- W1983565617
- Cited by
- 190
- References
- 11
- FWCI
- 5.69
- Type
- journal article
- Language
- en
- Open access
- gold
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