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3. Upregulation of TET2 and Resistance to DNA Methyltransferase (DNMT) Inhibitors in DNMT1 -Deleted Cancer Cells.

Author

Laranjeira, Angelo B. A., Nguyen, Dat, Pelosof, Lorraine C., Doroshow, James H., and Yang, Sherry X.

Subjects
TUMOR suppressor proteins, GENE expression, SUPPRESSOR cells, GENETIC regulation, RENAL cancer, P16 gene
Abstract

Simple Summary: Ten-eleven-translocation (TET) 2 is implicated in human cancers such as lung, breast, skin, and kidney cancers, T-cell lymphomas, and leukemia. It is unclear whether TET2 is involved in the re-expression of the p16 tumor suppressor, which was partially silenced by CDKN2A gene methylation. The effect of DNA methyltransferase (DNMT) 1 gene status on TET2 expression following DNMT inhibitor treatment remains unknown in cancer. We found that deleting the DNMT1 gene made cancer cells prone to increased TET2 expression and re-expression of p16 after drug treatment. TET2 is involved in the demethylation of the CDKN2A gene and activation of p16 expression, and concomitant resistance to DNMT inhibitors when DNMT1 is obliterated. The long-sought data for the first time revealed a link between TET2 expression and the activation of p16 expression. The findings should have an impact on reactivating tumor suppressors and cancer treatment. Background: Ten-eleven-translocation (TET) 2 is a member of the TET family of proteins (TET1-3). DNMT1 gene deletion confers resistance to DNA methyltransferase (DNMT) inhibitors in colorectal, breast, and ovarian cancer cells. Currently, the effect of DNMT1 gene status on TET2 phenotype following DNMT inhibitor treatment is unclear in human malignancies. Methods: Human colorectal carcinoma HCT116 cells (DNMT+/+) and their isogenic DNMT1 knockout (DNMT1–/–) counterpart were treated with DNMT inhibitors. Expression of TET2 and tumor suppressor (p16ink4A and p15ink4B) proteins were examined by Western blot. Apoptosis and CDKN2A promoter demethylation following drug treatment were detected by Annexin-V apoptosis assay and methylation-specific PCR. Results: TET2 expression was robustly increased in DNMT1−/− cells by 0.5 µM and 5 µM decitabine and azacitidine treatment. Augmentation of TET2 expression was accompanied by re-expression of p16ink4A and p15ink4B proteins and CDKN2A promoter demethylation. TET2 upregulation and tumor suppressor re-expression were associated with resistance conferred by DNMT1 deletion. Treatment with 5-aza-4′-thio-2′-deoxycytidine at a low 0.5 µM dose only upregulated TET2 and reduced CDKN2A promoter methylation, and re-expression of p16ink4A in DNMT1−/− cells. DNMT inhibitors showed minimal effects on TET2 upregulation and re-expression of tumor suppressor proteins in cells with intact DNMT1. Conclusions: DNMT1 gene deletion made cancer cells prone to TET2 upregulation and activation of tumor suppressor expression upon DNMT inhibitor challenge. TET2 augmentation is concomitant with resistance to DNMT inhibitors in a DNMT1-deleted state. [ABSTRACT FROM AUTHOR]

Published
2024
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10. Data from DNA Methyltransferase Inhibitor, Zebularine, Delays Tumor Growth and Induces Apoptosis in a Genetically Engineered Mouse Model of Breast Cancer

Author

Chen, Min, primary, Shabashvili, Daniel, primary, Nawab, Akbar, primary, Yang, Sherry X., primary, Dyer, Lisa M., primary, Brown, Kevin D., primary, Hollingshead, Melinda, primary, Hunter, Kent W., primary, Kaye, Frederic J., primary, Hochwald, Steven N., primary, Marquez, Victor E., primary, Steeg, Patricia, primary, and Zajac-Kaye, Maria, primary

Published
2023
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11. Supplementary Table 2 from DNA Methyltransferase Inhibitor, Zebularine, Delays Tumor Growth and Induces Apoptosis in a Genetically Engineered Mouse Model of Breast Cancer

Author

Chen, Min, primary, Shabashvili, Daniel, primary, Nawab, Akbar, primary, Yang, Sherry X., primary, Dyer, Lisa M., primary, Brown, Kevin D., primary, Hollingshead, Melinda, primary, Hunter, Kent W., primary, Kaye, Frederic J., primary, Hochwald, Steven N., primary, Marquez, Victor E., primary, Steeg, Patricia, primary, and Zajac-Kaye, Maria, primary

Published
2023
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12. Supplementary Table 7 from DNA Methyltransferase Inhibitor, Zebularine, Delays Tumor Growth and Induces Apoptosis in a Genetically Engineered Mouse Model of Breast Cancer

Author

Chen, Min, primary, Shabashvili, Daniel, primary, Nawab, Akbar, primary, Yang, Sherry X., primary, Dyer, Lisa M., primary, Brown, Kevin D., primary, Hollingshead, Melinda, primary, Hunter, Kent W., primary, Kaye, Frederic J., primary, Hochwald, Steven N., primary, Marquez, Victor E., primary, Steeg, Patricia, primary, and Zajac-Kaye, Maria, primary

Published
2023
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13. Supplementary Table 5 from DNA Methyltransferase Inhibitor, Zebularine, Delays Tumor Growth and Induces Apoptosis in a Genetically Engineered Mouse Model of Breast Cancer

Author

Chen, Min, primary, Shabashvili, Daniel, primary, Nawab, Akbar, primary, Yang, Sherry X., primary, Dyer, Lisa M., primary, Brown, Kevin D., primary, Hollingshead, Melinda, primary, Hunter, Kent W., primary, Kaye, Frederic J., primary, Hochwald, Steven N., primary, Marquez, Victor E., primary, Steeg, Patricia, primary, and Zajac-Kaye, Maria, primary

Published
2023
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14. Supplementary Table 1 from DNA Methyltransferase Inhibitor, Zebularine, Delays Tumor Growth and Induces Apoptosis in a Genetically Engineered Mouse Model of Breast Cancer

Author

Chen, Min, primary, Shabashvili, Daniel, primary, Nawab, Akbar, primary, Yang, Sherry X., primary, Dyer, Lisa M., primary, Brown, Kevin D., primary, Hollingshead, Melinda, primary, Hunter, Kent W., primary, Kaye, Frederic J., primary, Hochwald, Steven N., primary, Marquez, Victor E., primary, Steeg, Patricia, primary, and Zajac-Kaye, Maria, primary

Published
2023
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15. Supplementary Table 3 from DNA Methyltransferase Inhibitor, Zebularine, Delays Tumor Growth and Induces Apoptosis in a Genetically Engineered Mouse Model of Breast Cancer

Author

Chen, Min, primary, Shabashvili, Daniel, primary, Nawab, Akbar, primary, Yang, Sherry X., primary, Dyer, Lisa M., primary, Brown, Kevin D., primary, Hollingshead, Melinda, primary, Hunter, Kent W., primary, Kaye, Frederic J., primary, Hochwald, Steven N., primary, Marquez, Victor E., primary, Steeg, Patricia, primary, and Zajac-Kaye, Maria, primary

Published
2023
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16. Supplementary Table 4 from DNA Methyltransferase Inhibitor, Zebularine, Delays Tumor Growth and Induces Apoptosis in a Genetically Engineered Mouse Model of Breast Cancer

Author

Chen, Min, primary, Shabashvili, Daniel, primary, Nawab, Akbar, primary, Yang, Sherry X., primary, Dyer, Lisa M., primary, Brown, Kevin D., primary, Hollingshead, Melinda, primary, Hunter, Kent W., primary, Kaye, Frederic J., primary, Hochwald, Steven N., primary, Marquez, Victor E., primary, Steeg, Patricia, primary, and Zajac-Kaye, Maria, primary

Published
2023
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17. Supplementary Table 6 from DNA Methyltransferase Inhibitor, Zebularine, Delays Tumor Growth and Induces Apoptosis in a Genetically Engineered Mouse Model of Breast Cancer

Author

Chen, Min, primary, Shabashvili, Daniel, primary, Nawab, Akbar, primary, Yang, Sherry X., primary, Dyer, Lisa M., primary, Brown, Kevin D., primary, Hollingshead, Melinda, primary, Hunter, Kent W., primary, Kaye, Frederic J., primary, Hochwald, Steven N., primary, Marquez, Victor E., primary, Steeg, Patricia, primary, and Zajac-Kaye, Maria, primary

Published
2023
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18. Supplementary Figure 3 from Identification and Analysis of In Vivo VEGF Downstream Markers Link VEGF Pathway Activity with Efficacy of Anti-VEGF Therapies

Author

Brauer, Matthew J., primary, Zhuang, Guanglei, primary, Schmidt, Maike, primary, Yao, Jenny, primary, Wu, Xiumin, primary, Kaminker, Joshua S., primary, Jurinka, Stefanie S., primary, Kolumam, Ganesh, primary, Chung, Alicia S., primary, Jubb, Adrian, primary, Modrusan, Zora, primary, Ozawa, Tomoko, primary, James, C. David, primary, Phillips, Heidi, primary, Haley, Benjamin, primary, Tam, Rachel N.W., primary, Clermont, Anne C., primary, Cheng, Jason H., primary, Yang, Sherry X., primary, Swain, Sandra M., primary, Chen, Daniel, primary, Scherer, Stefan J., primary, Koeppen, Hartmut, primary, Yeh, Ru-Fang, primary, Yue, Peng, primary, Stephan, Jean-Philippe, primary, Hegde, Priti, primary, Ferrara, Napoleone, primary, Singh, Mallika, primary, and Bais, Carlos, primary

Published
2023
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20. Supplementary Figure 1 from Identification and Analysis of In Vivo VEGF Downstream Markers Link VEGF Pathway Activity with Efficacy of Anti-VEGF Therapies

Author

Brauer, Matthew J., primary, Zhuang, Guanglei, primary, Schmidt, Maike, primary, Yao, Jenny, primary, Wu, Xiumin, primary, Kaminker, Joshua S., primary, Jurinka, Stefanie S., primary, Kolumam, Ganesh, primary, Chung, Alicia S., primary, Jubb, Adrian, primary, Modrusan, Zora, primary, Ozawa, Tomoko, primary, James, C. David, primary, Phillips, Heidi, primary, Haley, Benjamin, primary, Tam, Rachel N.W., primary, Clermont, Anne C., primary, Cheng, Jason H., primary, Yang, Sherry X., primary, Swain, Sandra M., primary, Chen, Daniel, primary, Scherer, Stefan J., primary, Koeppen, Hartmut, primary, Yeh, Ru-Fang, primary, Yue, Peng, primary, Stephan, Jean-Philippe, primary, Hegde, Priti, primary, Ferrara, Napoleone, primary, Singh, Mallika, primary, and Bais, Carlos, primary

Published
2023
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21. Supplementary Methods, Tables 1 - 3 from Identification and Analysis of In Vivo VEGF Downstream Markers Link VEGF Pathway Activity with Efficacy of Anti-VEGF Therapies

Author

Brauer, Matthew J., primary, Zhuang, Guanglei, primary, Schmidt, Maike, primary, Yao, Jenny, primary, Wu, Xiumin, primary, Kaminker, Joshua S., primary, Jurinka, Stefanie S., primary, Kolumam, Ganesh, primary, Chung, Alicia S., primary, Jubb, Adrian, primary, Modrusan, Zora, primary, Ozawa, Tomoko, primary, James, C. David, primary, Phillips, Heidi, primary, Haley, Benjamin, primary, Tam, Rachel N.W., primary, Clermont, Anne C., primary, Cheng, Jason H., primary, Yang, Sherry X., primary, Swain, Sandra M., primary, Chen, Daniel, primary, Scherer, Stefan J., primary, Koeppen, Hartmut, primary, Yeh, Ru-Fang, primary, Yue, Peng, primary, Stephan, Jean-Philippe, primary, Hegde, Priti, primary, Ferrara, Napoleone, primary, Singh, Mallika, primary, and Bais, Carlos, primary

Published
2023
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22. Supplementary Figure 2 from Identification and Analysis of In Vivo VEGF Downstream Markers Link VEGF Pathway Activity with Efficacy of Anti-VEGF Therapies

Author

Brauer, Matthew J., primary, Zhuang, Guanglei, primary, Schmidt, Maike, primary, Yao, Jenny, primary, Wu, Xiumin, primary, Kaminker, Joshua S., primary, Jurinka, Stefanie S., primary, Kolumam, Ganesh, primary, Chung, Alicia S., primary, Jubb, Adrian, primary, Modrusan, Zora, primary, Ozawa, Tomoko, primary, James, C. David, primary, Phillips, Heidi, primary, Haley, Benjamin, primary, Tam, Rachel N.W., primary, Clermont, Anne C., primary, Cheng, Jason H., primary, Yang, Sherry X., primary, Swain, Sandra M., primary, Chen, Daniel, primary, Scherer, Stefan J., primary, Koeppen, Hartmut, primary, Yeh, Ru-Fang, primary, Yue, Peng, primary, Stephan, Jean-Philippe, primary, Hegde, Priti, primary, Ferrara, Napoleone, primary, Singh, Mallika, primary, and Bais, Carlos, primary

Published
2023
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25. Supplementary Figure 6 from Identification and Analysis of In Vivo VEGF Downstream Markers Link VEGF Pathway Activity with Efficacy of Anti-VEGF Therapies

Author

Brauer, Matthew J., primary, Zhuang, Guanglei, primary, Schmidt, Maike, primary, Yao, Jenny, primary, Wu, Xiumin, primary, Kaminker, Joshua S., primary, Jurinka, Stefanie S., primary, Kolumam, Ganesh, primary, Chung, Alicia S., primary, Jubb, Adrian, primary, Modrusan, Zora, primary, Ozawa, Tomoko, primary, James, C. David, primary, Phillips, Heidi, primary, Haley, Benjamin, primary, Tam, Rachel N.W., primary, Clermont, Anne C., primary, Cheng, Jason H., primary, Yang, Sherry X., primary, Swain, Sandra M., primary, Chen, Daniel, primary, Scherer, Stefan J., primary, Koeppen, Hartmut, primary, Yeh, Ru-Fang, primary, Yue, Peng, primary, Stephan, Jean-Philippe, primary, Hegde, Priti, primary, Ferrara, Napoleone, primary, Singh, Mallika, primary, and Bais, Carlos, primary

Published
2023
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26. Supplementary Figure 5 from Identification and Analysis of In Vivo VEGF Downstream Markers Link VEGF Pathway Activity with Efficacy of Anti-VEGF Therapies

Author

Brauer, Matthew J., primary, Zhuang, Guanglei, primary, Schmidt, Maike, primary, Yao, Jenny, primary, Wu, Xiumin, primary, Kaminker, Joshua S., primary, Jurinka, Stefanie S., primary, Kolumam, Ganesh, primary, Chung, Alicia S., primary, Jubb, Adrian, primary, Modrusan, Zora, primary, Ozawa, Tomoko, primary, James, C. David, primary, Phillips, Heidi, primary, Haley, Benjamin, primary, Tam, Rachel N.W., primary, Clermont, Anne C., primary, Cheng, Jason H., primary, Yang, Sherry X., primary, Swain, Sandra M., primary, Chen, Daniel, primary, Scherer, Stefan J., primary, Koeppen, Hartmut, primary, Yeh, Ru-Fang, primary, Yue, Peng, primary, Stephan, Jean-Philippe, primary, Hegde, Priti, primary, Ferrara, Napoleone, primary, Singh, Mallika, primary, and Bais, Carlos, primary

Published
2023
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27. Supplementary Figure 4 from Identification and Analysis of In Vivo VEGF Downstream Markers Link VEGF Pathway Activity with Efficacy of Anti-VEGF Therapies

Author

Brauer, Matthew J., primary, Zhuang, Guanglei, primary, Schmidt, Maike, primary, Yao, Jenny, primary, Wu, Xiumin, primary, Kaminker, Joshua S., primary, Jurinka, Stefanie S., primary, Kolumam, Ganesh, primary, Chung, Alicia S., primary, Jubb, Adrian, primary, Modrusan, Zora, primary, Ozawa, Tomoko, primary, James, C. David, primary, Phillips, Heidi, primary, Haley, Benjamin, primary, Tam, Rachel N.W., primary, Clermont, Anne C., primary, Cheng, Jason H., primary, Yang, Sherry X., primary, Swain, Sandra M., primary, Chen, Daniel, primary, Scherer, Stefan J., primary, Koeppen, Hartmut, primary, Yeh, Ru-Fang, primary, Yue, Peng, primary, Stephan, Jean-Philippe, primary, Hegde, Priti, primary, Ferrara, Napoleone, primary, Singh, Mallika, primary, and Bais, Carlos, primary

Published
2023
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34. Additional file 1 of TET2 and DNMT3A mutations and exceptional response to 4′-thio-2′-deoxycytidine in human solid tumor models

Author

Yang, Sherry X., Hollingshead, Melinda, Rubinstein, Larry, Nguyen, Dat, Larenjeira, Angelo B. A., Kinders, Robert J., Difilippantonio, Michael, and Doroshow, James H.

Abstract

Additional file 1: Fig. S1. Inhibition of growth and TET2, and cell cycle arrest by T-dCyd in human solid tumor cell lines. Fig. S2. Effects of T-dCyd on DNMT3A/TET2-mutant NCI-H23 xenograft tumors in mice treated with 2 mg/kg T-dCyd by immunohistochemical and microscopic analyses (6 tumor samples per group). Fig. S3. Effects of T-dCyd on the induction of apoptosis in NCI-H23 cells. Fig. S4. Effects of T-dCyd on TET2 expression in DNMT3A/TET2-mutant NCI-H23 xenograft tumors.

Published
2021
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42. Antiangiogenic and Antitumor Effects of Bevacizumab in Patients With Inflammatory and Locally Advanced Breast Cancer

Author

Wedam, Suparna Bonthala, Low, Jennifer A., Yang, Sherry X., Chow, Catherine K., Choyke, Peter, Danforth, David, Hewitt, Stephen M., Berman, Arlene, Steinberg, Seth M., Liewehr, David J., Plehn, Jonathan, Doshi, Arpi, Thomasson, Dave, McCarthy, Nicole, Koeppen, Hartmut, Sherman, Mark, Zujewski, JoAnne, Camphausen, Kevin, Chen, Helen, and Swain, Sandra M.

Published
2006
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