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Discovery of a selective TRF2 inhibitor FKB04 induced telomere shortening and senescence in liver cancer cells

Acta Pharmacologica Sinica (2024)Cite this article

Abstract

Telomere repeat binding factor 2 (TRF2), a critical element of the shelterin complex, plays a vital role in the maintenance of genome integrity. TRF2 overexpression is found in a wide range of malignant cancers, whereas its down-regulation could cause cell death. Despite its potential role, the selectively small-molecule inhibitors of TRF2 and its therapeutic effects on liver cancer remain largely unknown. Our clinical data combined with bioinformatic analysis demonstrated that TRF2 is overexpressed in liver cancer and that high expression is associated with poor prognosis. Flavokavain B derivative FKB04 potently inhibited TRF2 expression in liver cancer cells while having limited effects on the other five shelterin subunits. Moreover, FKB04 treatment induced telomere shortening and increased the amounts of telomere-free ends, leading to the destruction of T-loop structure. Consequently, FKB04 promoted liver cancer cell senescence without modulating apoptosis levels. In corroboration with these findings, FKB04 inhibited tumor cell growth by promoting telomeric TRF2 deficiency-induced telomere shortening in a mouse xenograft tumor model, with no obvious side effects. These results demonstrate that TRF2 is a potential therapeutic target for liver cancer and suggest that FKB04 may be a selective small-molecule inhibitor of TRF2, showing promise in the treatment of liver cancer.

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Fig. 1: TRF2 is a valuable predictive marker in liver cancer progression and prognosis.
Fig. 2: FKB04 induces a senescent phenotype in liver cancer cells.
Fig. 3: FKB04 disrupts the telomere maintenance mechanism in liver cancer cells.
Fig. 4: FKB04 does not cause substantial telomeric DNA damage but causes T-loop deficiency.
Fig. 5: FKB04 impairs the protective effect of TRF2 on telomeres.
Fig. 6: FKB04 inhibits the growth of Huh-7 xenograft tumors in mice by promoting TRF2 function deficiency.

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Acknowledgements

This work was supported by the National Natural Science Foundation of China (82273788, 81973168, 82273995), the Natural Science Foundation of Zhejiang Province (LZ22H300002), Wenzhou Science and Technology Plan Project (Y2023180, Y20220200, Y20220195), and Wenzhou Key Laboratory of Research and Transformation of Chinese Medicine. We also thank the Scientific Research Center of Wenzhou Medical University for the consultation and instrument availability that supported this work.

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  1. These authors contributed equally: Yin-da Qiu, Qi Yan, Yi Wang

Authors and Affiliations

  1. School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, China

    Yin-da Qiu, Qi Yan, Yi Wang, Yan-fei Ye, Yan Wang, Meng-ying Wang, Pei-pei Wang, Shu-yuan Zhang, Da-long Wang, Hao Yan, Yun-jie Zhao, Le-hao Huang, Kun Wang, Xiao-hui Zheng & Zhi-guo Liu

  2. College of Pharmacy, Chonnam National University, Gwangju, 61186, Republic of Korea

    Yin-da Qiu & Namki Cho

  3. Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou, 325035, China

    Jing Ruan

  4. Oujiang Laboratory, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou, 325035, China

    Zhi-guo Liu

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Contributions

ZGL and XHZ designed the study and supervised the experimental work; YDQ, QY, Yi Wang, YFY, Yan Wang, MYW, PPW, and DLW performed experiments; SYZ, HY, and JR analyzed data; ZGL, XHZ, and YDQ wrote the manuscript; YJZ, LHH, NC, and KW polished the language of the manuscript. All authors read and approved the final version of the manuscript.

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Correspondence to Jing Ruan, Xiao-hui Zheng or Zhi-guo Liu.

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Qiu, Yd., Yan, Q., Wang, Y. et al. Discovery of a selective TRF2 inhibitor FKB04 induced telomere shortening and senescence in liver cancer cells. Acta Pharmacol Sin (2024). https://doi.org/10.1038/s41401-024-01243-6

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