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

Yin-da Qiu1,2, Qi Yan1, Yi Wang1, Yan-fei Ye1, Yan Wang1, Meng-ying Wang1, Pei-pei Wang1, Shu-yuan Zhang1, Da-long Wang1, Hao Yan1, Jing Ruan3, Yun-jie Zhao1, Le-hao Huang1, Namki Cho2, Kun Wang1, Xiao-hui Zheng1, Zhi-guo Liu1,4
1 School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325035, China
2 College of Pharmacy, Chonnam National University, Gwangju 61186, Republic of Korea
3 Department of Pathology, The First Affiliated Hospital of Wenzhou Medical University, Wenzhou 325035, China
4 Oujiang Laboratory, School of Pharmaceutical Science, Wenzhou Medical University, Wenzhou 325035, China
Correspondence to: Jing Ruan:, Xiao-hui Zheng:, Zhi-guo Liu:,
DOI: 10.1038/s41401-024-01243-6
Received: 10 September 2023
Accepted: 11 February 2024
Advance online: 4 March 2024


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.

Keywords: liver cancer; cell senescence; telomere; TRF2; flavokavain B derivative FKB04

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