2. Academic Validation
  3. The ATM and ATR kinases regulate centrosome clustering and tumor recurrence by targeting KIFC1 phosphorylation

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

  • Nat Commun. 2021 Jan 4;12(1):20. doi: 10.1038/s41467-020-20208-x.
Guangjian Fan 1,  Lianhui Sun 1,  Ling Meng 2,  Chen Hu 1,  Xing Wang 1,  Zhan Shi 1,  Congli Hu 1,  Yang Han 1,  Qingqing Yang 1,  Liu Cao 3,  Xiaohong Zhang 4,  Yan Zhang 5,  Xianmin Song 5,  Shujie Xia 6,  Baokun He 7,  Shengping Zhang 8,  Chuangui Wang 9
Affiliations

Affiliations

  • 1 Translational Medicine Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 201620, Shanghai, China.
  • 2 Department of Pulmonary and Critical Care Medicine, The Second Affiliated Hospital of Shandong First Medical University, 271000, Shandong, China.
  • 3 Key Laboratory of Medical Cell Biology, College of Translational Medicine, China Medical University, 110000, Shenyang, China.
  • 4 Department of Oncology, Karmanos Cancer Institute, Wayne State University School of Medicine, 4100 John R., Detroit, MI, 48201, USA.
  • 5 Department of Hematology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 201620, Shanghai, China.
  • 6 Department of Urology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine; Institute of Urology, Shanghai Jiao Tong University, 200080, Shanghai, China.
  • 7 Department of Gastroenterology, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 201620, Shanghai, China.
  • 8 Translational Medicine Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 201620, Shanghai, China. spzhang2019@126.com.
  • 9 Translational Medicine Center, Shanghai General Hospital, Shanghai Jiao Tong University School of Medicine, 201620, Shanghai, China. cgwang2016@sjtu.edu.cn.
PMID: 33397932 DOI: 10.1038/s41467-020-20208-x
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.

Figures
Products