Research Paper Volume 12, Issue 14 pp 14341—14354
LKB1 inactivation leads to centromere defects and genome instability via p53-dependent upregulation of survivin
- 1 State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China
- 2 School of Life Sciences, Henan University, Kaifeng, Henan Province 475004, China
- 3 Department of General Surgery, The Second Affiliated Hospital, Soochow University, Suzhou 215004, China
- 4 Department of Pathology, The Second Affiliated Hospital, Soochow University, Suzhou 215004, China
- 5 Department of Urology, The Second Affiliated Hospital, Soochow University, Suzhou 215004, China
- 6 Department of Medicine, University of Alabama at Birmingham, Birmingham, AL 35294, USA
Received: January 21, 2020 Accepted: April 17, 2020 Published: July 16, 2020https://doi.org/10.18632/aging.103473
How to Cite
Copyright © 2020 Jin et al. This is an open-access article distributed under the terms of the Creative Commons Attribution License (CC BY 3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
Inactivating mutations in the liver kinase B1 (LKB1) tumor suppressor gene underlie Peutz-Jeghers syndrome (PJS) and occur frequently in various human cancers. We previously showed that LKB1 regulates centrosome duplication via PLK1. Here, we report that LKB1 further helps to maintain genomic stability through negative regulation of survivin, a member of the chromosomal passenger complex (CPC) that mediates CPC targeting to the centromere. We found that loss of LKB1 led to accumulation of misaligned and lagging chromosomes at metaphase and anaphase and increased the appearance of multi- and micro-nucleated cells. Ectopic LKB1 expression reduced these features and improved mitotic fidelity in LKB1-deficient cells. Through pharmacological and genetic manipulations, we showed that LKB1-mediated repression of survivin is independent of AMPK, but requires p53. Consistent with the key influence of LKB1 on survivin expression, immunohistochemical analysis indicated that survivin is highly expressed in intestinal polyps from a PJS patient. Lastly, we reaffirm a potential therapeutic avenue to treat LKB1-mutated tumors by demonstrating the increased sensitivity to survivin inhibitors of LKB1-deficient cells.