1. Key Laboratory of Carcinogenesis and Translational Research (Ministry of Education), Beijing Key Laboratory of Protein Posttranslational Modifications and Cell Function; Department of Biochemistry and Molecular Biology, School of Basic Medical Sciences, Peking University Health Science Center, Beijing 100191, China; 2. Department of Biochemistry and Molecular Biology, School of Medicine, Shenzhen University, Shenzhen 518060, China; 3. Department of Colorectal Surgery, Peking University Cancer Hospital & Institute, Beijing 100142, China; 4. Department of Medical Genetics, Peking University Health Science Center, Beijing 100191, China; 5. Institute of Systems Biomedicine, Department of Radiation Medicine, School of Basic Medical Sciences, Peking University, Beijing 100191, China; 6. Peking University-Tsinghua University Center for Life Sciences, Beijing 100871, China. * These authors are co-first authors
✉ Corresponding authors: Wei-Guo Zhu, Tel: 0086-10-82802235; Fax: 86-10-82805079; Email: zhuweiguoedu.cn or zhuweiguoedu.cn or Haiying Wang at wendyedu.cn
Citation:
Tang M, Lu X, Zhang C, Du C, Cao L, Hou T, Li Z, Tu B, Cao Z, Li Y, Chen Y, Jiang L, Wang H, Wang L, Liu B, Xu X, Luo J, Wang J, Gu J, Wang H, Zhu WG. Downregulation of SIRT7 by 5-fluorouracil induces radiosensitivity in human colorectal cancer. Theranostics 2017; 7(5):1346-1359. doi:10.7150/thno.18804. https://www.thno.org/v07p1346.htm
5-Fluorouracil (5-FU) combined with radiotherapy is a common treatment strategy to treat human cancers, but the underlying mechanisms of this combination treatment remain unclear. Here, we report that NAD+-dependent deacetylase sirtuin-7 (SIRT7) protein levels were decreased due to 5-FU exposure rendering colorectal cancer cells sensitive to radiation. We found that SIRT7 downregulation was mediated via a Tat-binding Protein 1 (TBP1) proteasome-dependent pathway. Specifically, TBP1 was dephosphorylated at tyrosine 381 upon 5-FU treatment, which enhanced its direct interaction with SIRT7 and targeted it for degradation. Depletion of SIRT7 in cultured colorectal cancer cells induced radiosensitivity triggering cell death. Interestingly, decreased levels of SIRT7 mediated by 5-FU correlated well with improved therapeutic effect in patients with rectal cancer and with inhibited tumor growth in immune-compromised mice post-irradiation. Taken together, these data suggest that 5-FU induces radiosensitivity via SIRT7 degradation to favor a cell death pathway in targeted cancer cells. Thus, downregulation of SIRT7 could be a promising pharmacologic strategy to increase the effectiveness of chemoradiation therapy in cancer patients.
Tang, M., Lu, X., Zhang, C., Du, C., Cao, L., Hou, T., Li, Z., Tu, B., Cao, Z., Li, Y., Chen, Y., Jiang, L., Wang, H., Wang, L., Liu, B., Xu, X., Luo, J., Wang, J., Gu, J., Wang, H., Zhu, W.G. (2017). Downregulation of SIRT7 by 5-fluorouracil induces radiosensitivity in human colorectal cancer. Theranostics, 7(5), 1346-1359. https://doi.org/10.7150/thno.18804.
ACS
Tang, M.; Lu, X.; Zhang, C.; Du, C.; Cao, L.; Hou, T.; Li, Z.; Tu, B.; Cao, Z.; Li, Y.; Chen, Y.; Jiang, L.; Wang, H.; Wang, L.; Liu, B.; Xu, X.; Luo, J.; Wang, J.; Gu, J.; Wang, H.; Zhu, W.G. Downregulation of SIRT7 by 5-fluorouracil induces radiosensitivity in human colorectal cancer. Theranostics 2017, 7 (5), 1346-1359. DOI: 10.7150/thno.18804.
NLM
Tang M, Lu X, Zhang C, Du C, Cao L, Hou T, Li Z, Tu B, Cao Z, Li Y, Chen Y, Jiang L, Wang H, Wang L, Liu B, Xu X, Luo J, Wang J, Gu J, Wang H, Zhu WG. Downregulation of SIRT7 by 5-fluorouracil induces radiosensitivity in human colorectal cancer. Theranostics 2017; 7(5):1346-1359. doi:10.7150/thno.18804. https://www.thno.org/v07p1346.htm
CSE
Tang M, Lu X, Zhang C, Du C, Cao L, Hou T, Li Z, Tu B, Cao Z, Li Y, Chen Y, Jiang L, Wang H, Wang L, Liu B, Xu X, Luo J, Wang J, Gu J, Wang H, Zhu WG. 2017. Downregulation of SIRT7 by 5-fluorouracil induces radiosensitivity in human colorectal cancer. Theranostics. 7(5):1346-1359.
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