HURP binding to the vinca domain of β-tubulin accounts for cancer drug resistance

Athira Saju, Po-Pang Chen, Tzu-Han Weng, Su-Yi Tsai, Akihiro Tanaka, Yu-Ting Tseng, Chih-Chia Chang, Chun-Hsiung Wang, Yuta Shimamoto and Kuo-Chiang Hsia ()
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Athira Saju: Academia Sinica
Po-Pang Chen: Academia Sinica
Tzu-Han Weng: National Taiwan University
Su-Yi Tsai: National Taiwan University
Akihiro Tanaka: National Institute of Genetics
Yu-Ting Tseng: Academia Sinica
Chih-Chia Chang: Academia Sinica
Chun-Hsiung Wang: Academia Sinica
Yuta Shimamoto: National Institute of Genetics
Kuo-Chiang Hsia: Academia Sinica

Nature Communications, 2024, vol. 15, issue 1, 1-20

Abstract: Abstract Vinca alkaloids, a class of tubulin-binding agent, are widely used in treating cancer, yet the emerging resistance compromises their efficacy. Hepatoma up-regulated protein (HURP), a microtubule-associated protein displaying heightened expression across various cancer types, reduces cancer cells’ sensitivity to vinca-alkaloid drugs upon overexpression. However, the molecular basis behind this drug resistance remains unknown. Here we discover a tubulin-binding domain within HURP, and establish its role in regulating microtubule growth. Cryo-EM analysis reveals interactions between HURP’s tubulin-binding domain and the vinca domain on β-tubulin -- the site targeted by vinca alkaloid drugs. Importantly, HURP competes directly with vinorelbine, a vinca alkaloid-based chemotherapeutic agent, countering microtubule growth defects caused by vinorelbine both in vitro and in vivo. Our findings elucidate a mechanism driving drug resistance in HURP-overexpressing cancer cells and emphasize HURP tubulin-binding domain’s role in mitotic spindle assembly. This underscores its potential as a therapeutic target to improve cancer treatment.

Date: 2024
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DOI: 10.1038/s41467-024-53139-y

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