Nuclear Nestin deficiency drives tumor senescence via lamin A/C-dependent nuclear deformation

Yanan Zhang, Jiancheng Wang, Weijun Huang, Jianye Cai, Junhui Ba, Yi Wang, Qiong Ke, Yinong Huang, Xin Liu, Yuan Qiu, Qiying Lu, Xin Sui, Yue Shi, Tao Wang, Huiyong Shen, Yuanjun Guan, Ying Zhou, Yuan Chen, Maosheng Wang () and Andy Peng Xiang ()
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Yanan Zhang: Sun Yat-sen University
Jiancheng Wang: Sun Yat-sen University
Weijun Huang: Sun Yat-Sen University
Jianye Cai: Sun Yat-Sen University
Junhui Ba: The Third Affiliated Hospital of Sun Yat-sen University
Yi Wang: Sun Yat-sen University
Qiong Ke: Sun Yat-Sen University
Yinong Huang: Sun Yat-sen University
Xin Liu: Sun Yat-sen University
Yuan Qiu: Sun Yat-sen University
Qiying Lu: Sun Yat-sen University
Xin Sui: Sun Yat-sen University
Yue Shi: Sun Yat-sen University
Tao Wang: Sun Yat-sen University
Huiyong Shen: Sun Yat-sen University
Yuanjun Guan: Sun Yat-Sen University
Ying Zhou: The First Affiliated Hospital of Wenzhou Medical University
Yuan Chen: Sun Yat-Sen University
Maosheng Wang: Gaozhou People’s Hospital
Andy Peng Xiang: Sun Yat-sen University

Nature Communications, 2018, vol. 9, issue 1, 1-14

Abstract: Abstract Emerging evidence has revealed that Nestin not only serves as a biomarker for multipotent stem cells, but also regulates cell proliferation and invasion in various tumors. However, the mechanistic contributions of Nestin to cancer pathogenesis are still unknown. In the present study, previously thought to reside exclusively in the cytoplasm, Nestin can also be found in the nucleus and participate in protecting tumor cells against cellular senescence. Specifically, we reveal that Nestin has a nuclear localization signal (aa318–aa347) at the downstream of rod domain. We then find nuclear Nestin could interact with lamin A/C. Mechanistic investigations demonstrate that Nestin depletion results in the activation of cyclin-dependent kinase 5 (Cdk5), which causes the phosphorylation of lamin A/C (mainly at S392 site) and its subsequent translocation to the cytoplasm for degradation. The findings establish a role for nuclear Nestin in tumor senescence, which involves its nucleus-localized form and interaction with lamin A/C.

Date: 2018
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DOI: 10.1038/s41467-018-05808-y

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