The ATM and ATR kinases regulate centrosome clustering and tumor recurrence by targeting KIFC1 phosphorylation

Guangjian Fan, Lianhui Sun, Ling Meng, Chen Hu, Xing Wang, Zhan Shi, Congli Hu, Yang Han, Qingqing Yang, Liu Cao, Xiaohong Zhang, Yan Zhang, Xianmin Song, Shujie Xia, Baokun He, Shengping Zhang () and Chuangui Wang ()
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Guangjian Fan: Shanghai Jiao Tong University School of Medicine
Lianhui Sun: Shanghai Jiao Tong University School of Medicine
Ling Meng: The Second Affiliated Hospital of Shandong First Medical University
Chen Hu: Shanghai Jiao Tong University School of Medicine
Xing Wang: Shanghai Jiao Tong University School of Medicine
Zhan Shi: Shanghai Jiao Tong University School of Medicine
Congli Hu: Shanghai Jiao Tong University School of Medicine
Yang Han: Shanghai Jiao Tong University School of Medicine
Qingqing Yang: Shanghai Jiao Tong University School of Medicine
Liu Cao: China Medical University
Xiaohong Zhang: Wayne State University School of Medicine
Yan Zhang: Shanghai Jiao Tong University School of Medicine
Xianmin Song: Shanghai Jiao Tong University School of Medicine
Shujie Xia: Shanghai Jiao Tong University School of Medicine; Institute of Urology, Shanghai Jiao Tong University
Baokun He: Shanghai Jiao Tong University School of Medicine
Shengping Zhang: Shanghai Jiao Tong University School of Medicine
Chuangui Wang: Shanghai Jiao Tong University School of Medicine

Nature Communications, 2021, vol. 12, issue 1, 1-16

Abstract: Abstract Drug resistance and tumor recurrence are major challenges in cancer treatment. Cancer cells often display centrosome amplification. To maintain survival, cancer cells achieve bipolar division by clustering supernumerary centrosomes. Targeting centrosome clustering is therefore considered a promising therapeutic strategy. However, the regulatory mechanisms of centrosome clustering remain unclear. Here we report that KIFC1, a centrosome clustering regulator, is positively associated with tumor recurrence. Under DNA damaging treatments, the ATM and ATR kinases phosphorylate KIFC1 at Ser26 to selectively maintain the survival of cancer cells with amplified centrosomes via centrosome clustering, leading to drug resistance and tumor recurrence. Inhibition of KIFC1 phosphorylation represses centrosome clustering and tumor recurrence. This study identified KIFC1 as a prognostic tumor recurrence marker, and revealed that tumors can acquire therapeutic resistance and recurrence via triggering centrosome clustering under DNA damage stresses, suggesting that blocking KIFC1 phosphorylation may open a new vista for cancer therapy.

Date: 2021
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DOI: 10.1038/s41467-020-20208-x

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