HKUMed uncovers key mechanism linking microtubules and chemotherapy, enhancing cancer drug efficacy

A joint research team from the LKS Faculty of Medicine (HKUMed) and the Faculty of Science at the University of Hong Kong has uncovered an unexpected interaction between chemotherapeutic agents and a crucial efficacy marker. This pioneering study, recently published in Nature Structural & Molecular Biology (link to publication), sheds light on the complex interplay between taxanes—widely used chemotherapeutic drugs—and microtubule acetylation, a process vital for cancer cell sensitivity to treatment. In addition to deepening understanding of cancer biology, the study opens an avenue for innovative therapies aimed at enhancing patient outcomes and combating drug resistance, particularly for some of the most challenging malignancies, such as ovarian, breast, and lung cancers.

Background
Microtubules are hollow cylindrical structures that play a fundamental role in many biological functions. They are particularly important in cancer-related cellular processes, such as cell division and migration. This explains why many chemotherapeutic drugs, like taxanes, target microtubules for cancer treatment. Current studies have revealed that chemical modifications of microtubules can determine the sensitivity of cancer cells to drugs. Drug resistance has become a significant challenge in clinical cancer treatment.

One specific modification, microtubule acetylation, is catalysed by an enzyme called tubulin acetyltransferase and has been linked to the efficacy of paclitaxel, which is among the most successful chemotherapeutic agents under the class of taxanes for treating ovarian, breast, and lung cancers. However, the molecular mechanism by which tubulin acetyltransferases modify microtubules and interact with paclitaxel remains unknown. There is an urgent need for research to clarify these mechanisms to develop a novel therapeutic reagent.

Research methods and findings
The research team, led by Professor Jeff Ti Shih-Chieh from the School of Biomedical Sciences at HKUMed, has made a breakthrough in understanding how tubulin acetyltransferases recognise and modify microtubules. In collaboration with the School of Biological Sciences in the HKU Faculty of Science, the team generated recombinant proteins to restore different stages of the enzymatic reaction that leads to microtubule acetylation. Using high-resolution cryo-electron microscopy (cryo-EM) and single-molecule fluorescence microscopy, the team revealed the evolutionarily conserved role of taxane-binding pockets in the functions of tubulin acetyltransferases.

The study unravelled how tubulin acetyltransferases function within the hollow centre of microtubules. They found that reactions inside the microtubules are inhibited by paclitaxel. Further investigation showed that tubulin acetyltransferases employ anchors in the taxane-binding pocket to facilitate microtubule acetylation in the lumen. This finding enhances the understanding of the correlation between microtubule acetylation levels and paclitaxel-induced cytotoxicity in cancer cells and paves the way for developing strategies to modulate tubulin acetyltransferase activities for disease treatment.

Significance of the research
Microtubule acetylation is essential for many cellular functions and has been linked to various health conditions, including cancer and brain disorders. Until this study, the molecular mechanism by which tubulin acetyltransferases access and modify the target residue in the micrometre-long microtubules remained unknown. ‘We established the needed molecular insight that can serve as a foundation for future research aimed at resolving the current contradictory arguments on how increased microtubule acetylation levels affect paclitaxel-induced cytotoxicity in cancer cells,’ said Luo Jingyi, the lead author and a PhD candidate in the School of Biomedical Sciences.

Professor Ti emphasised the implications of this research for translational medicine. ‘By understanding the detailed mechanisms of microtubule modification, scientists can develop new therapies that target these processes,’ he said. ‘For example, modulators of tubulin acetyltransferases could become powerful tools for treating diseases associated with abnormal microtubule acetylation levels, such as certain cancers and neurodegenerative disorders like Huntington’s disease and Parkinson’s disease. Overall, this research marks a significant step forward in our understanding of cellular microtubule-based machinery and in setting the groundwork for innovative treatments that may improve patient outcomes and offer new hope for those battling various diseases.’

About the research team
The research team was led by Professor Jeff Ti Shih-Chieh, Assistant Professor, School of Biomedical Sciences, HKUMed, in collaboration with Professor Zhai Yuan-liang, former Associate Professor at the School of Biological Sciences, HKU Faculty of Science.

Acknowledgments
The study was funded by the General Research Fund and the Collaborative Research Fund from the Research Grants Council, and supported by the National Natural Science Foundation of China. The cryo-electron microscopy data was collected at the Biological Cryo-EM Center at The Hong Kong University of Science and Technology. Single-molecule fluorescence microscopy was performed at the Imaging and Flow Cytometry Core, Centre for PanorOmic Sciences, HKUMed.

Media enquiries
Please contact LKS Faculty of Medicine of The University of Hong Kong by email (medmedia@hku.hk).