Journal Article

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

Cao, Liu, Wang, Chuangui, He, Baokun, Wang, Xing, Hu, Chen, Han, Yang, Meng, Ling, Hu, Congli, Zhang, Xiaohong, Xia, Shujie, Sun, Lianhui, Zhang, Shengping, Shi, Zhan, Zhang, Yan, Song, Xianmin, Fan, Guangjian, Yang, Qingqing

2021

Overview

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. Centrosome clustering is a promising therapeutic target in cancer but how it is regulated remains unclear. Here, the authors show that in response to DNA damage, ATM/ATR stabilize the centrosome clustering regulator KIFC1 leading to increased clustering efficiency and tumour recurrence.

• Publisher: Nature Publishing Group UK,Nature Publishing Group,Nature Portfolio
• Subject: 13/109 / 14/1 / 14/19 / 631/67/1059 / 631/80/458/1733 / 631/80/641/1655 / 82/58 / 82/80 / Amino Acid Sequence / Amplification / Animals / Ataxia Telangiectasia Mutated Proteins - metabolism / Cancer / Cancer therapies / Cell Line, Tumor / Centrosome - metabolism / Centrosomes / Chromosomal Instability / Clustering / Damage / Deoxyribonucleic acid / DNA / DNA Damage / Drug resistance / Drug Resistance, Neoplasm / Humanities and Social Sciences / Humans / Kinases / Kinesins - chemistry / Kinesins - metabolism / Mice / multidisciplinary / Neoplasm Recurrence, Local - metabolism / Neoplasm Recurrence, Local - pathology / Phosphorylation / Phosphoserine - metabolism / Regulatory mechanisms (biology) / Science / Science (multidisciplinary) / Supernumerary / Survival / Tumors