Cell Cycle-Specific Regulation of Centrosome Clustering Dynamics in Cancer Cells by the Multifunctional Kinesin HSET

Sep 22, 2026

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Centrosome amplification in cancer cells produces excess centrosomes that cluster and decluster throughout the cell cycle, a process critical for tumorigenesis. The mitotic kinesin HSET is identified as a multifunctional regulator of these dynamics, acting beyond microtubule crosslinking to co-condensate with CDK5RAP2 and deliver it toward microtubule minus ends. This directed transport concentrates centrosomes at spindle poles, limits dispersal, and enables size-independent delivery that overcomes cytosolic viscosity. HSET’s ATP-independent self-assembly prevents declustering, preserving centrosome integrity, and supports its role as a cell cycle control layer with therapeutic potential.

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Introduction

Centrosome structure and duplication control

Cancer-associated supernumerary centrosomes

Centrosome coalescence and its cell-cycle reversal

Centrosomes as condensates and transport challenges

Advanced Science [www.advancedscience.com](www.advancedscience.com) RESEARCH ARTICLE Cell Cycle-Specific Regulation of Centrosome Clustering Dynamics in Cancer Cells by the Multifunctional Kinesin HSET Po-Pang Chen1, 2 Athira Saju1, 3 Chia-Chou Wu1 Tzu-Han Weng4 Su-Yi Tsai4 Tzu-Lun Huang1 Jia-Ying Su1 Chien-Ling Lin1 Yu-Chun Lin5 See-Yeun Ting1 Sheng-hong Chen1 Kuo-Chiang Hsia1, 2, 3 1 Institute of Molecular Biology, Academia Sinica, Taipei, Taiwan 2 Institute of Biochemistry and Molecular Biology, College of Life Sciences, National Yang-Ming Chiao-Tung University, Taipei, Taiwan 3Molecular and Cell Biology, Taiwan International Graduate Program and National Defense Medical Center, Taiwan 4 Department of Life Science, National Taiwan University, Taipei, Taiwan 5 Institute of Molecular Medicine National Tsing Hua University, Hsinchu, Taiwan Correspondence: Kuo-Chiang Hsia ([khsia@gate.sinica.edu.tw](khsia@gate.sinica.edu.tw)) Received: 9 December 2025 Revised: 20 February 2026 Accepted: 24 February 2026 Keywords: centrosome | cancer | kinesin HSET | microtubule ABSTRACT Centrosome amplification in cancer cells produces excess centrosomes that cluster and decluster throughout the cell cycle, a process critical for tumorigenesis. Here, we identify the mitotic kinesin HSET as a multifaceted regulator of these dynamics in cancer cells. Beyond microtubule crosslinking, HSET co-condensates with the centrosomal protein CDK5RAP2 and actively transports it toward microtubule minus ends. This directed delivery concentrates centrosomes at spindle poles, thereby limiting centrosome dispersal and contributing to centrosome coalescence. Notably, HSET-driven transport enables effective transport of CDK5RAP2 condensates, independently of size, thereby overcoming cytosolic viscosity to cluster large foci of pericentriolar material within cells. Furthermore, HSET’s ATP-independent self-assembly prevents centrosomal declustering, preserving centrosome integrity during mitotic progression. These activities position HSET as a critical regulator of centrosome clustering and integrity, with its mitosis-specific upregulation providing another layer of cell cycle control over centrosome assembly and underscoring its potential as a target for cancer therapeutics. 1 Introduction The centrosome consists ofa pair of cylindrical centrioles embedded in a protein-rich matrix known as the pericentriolar material (PCM) [1] . Various microtubule-nucleating factors, such as γ-tubulin ring complexes (γ-TuRCs), are deposited in the PCM [1–4], allowing the centrosome to function as a microtubuleorganizing center (MTOC) and establish a mitotic bipolar spindle. Precise control of centrosome duplication, limited to once per cell cycle, is necessary to establish bipolarity of the spindle [5, 6] . This bipolarity ensures accurate chromosome segregation during mitosis, a fundamental process for genomic stability [7] . The presence of supernumerary centrosomes is a common feature of cancer cells [8, 9] . Such aberrations can arise through several mechanisms, including centrosome over-duplication [8], centriole over-elongation [10, 11], or PCM fragmentation [12] . Loss of centrosome structural integrity drives PCM fragmentation, giving rise to acentriolar centrosomes, which retain microtubulenucleating capacity [12] . The presence of multiple centrosomes | Po-Pang Chen and Athira Saju contributed equally to this work.
| | --- | | This is an open access article under the terms of the Creative Commons Attribution License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited.
© 2026 The Author(s). Advanced Science published by Wiley-VCH GmbH | Advanced Science, 2026; 13:e74651 1 of 24 [https://doi.org/10.1002/advs.74651](https://doi.org/10.1002/advs.74651) can contribute to aneuploidy and chromosomal instability, which are critical drivers of intra-tumor het

FAQs

Why is centrosome clustering important in cancer cells?

Supernumerary centrosomes commonly arise in cancer and must be clustered into groups during mitosis to form a pseudo-bipolar spindle, enabling tumor initiation and progression.

What multifaceted role does HSET play in centrosome clustering dynamics?

HSET regulates these dynamics by microtubule crosslinking, co-condensation with CDK5RAP2, directed transport toward microtubule minus ends, and self-assembly that prevents declustering.

How does HSET overcome barriers related to cargo transport and cell-cycle regulation?

HSET-driven transport delivers CDK5RAP2 condensates independently of size, overcoming cytosolic viscosity, and its ATP-independent self-assembly preserves centrosome integrity during mitotic progression by preventing declustering.

Sep 22, 2026

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