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Theranostics 2017; 7(5):1346-1359. doi:10.7150/thno.18804 This issue Cite

Research Paper

Downregulation of SIRT7 by 5-fluorouracil induces radiosensitivity in human colorectal cancer

Ming Tang^1*, Xiaopeng Lu^1*, Chaohua Zhang^{1, 2}, Changzheng Du^{1, 3}, Linlin Cao¹, Tianyun Hou¹, Zhiming Li^{1, 2}, Bo Tu¹, Ziyang Cao^{1, 2}, Yinglu Li^{1, 2}, Yongcan Chen^{1, 2}, Lu Jiang¹, Hui Wang¹, Lina Wang¹, Baohua Liu², Xingzhi Xu², Jianyuan Luo⁴, Jiadong Wang⁵, Jin Gu³, Haiying Wang^1✉, Wei-Guo Zhu^{1, 2, 6✉}

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

Abstract

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.

Keywords: SIRT7, TBP1, 5-FU, phosphorylation, therapeutic effect.

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