LKB1 inactivation leads to centromere defects and genome instability via p53-dependent upregulation of survivin.

Abstract

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.

• Authors: Li-Yan Jin, Kui Zhao, Long-Jiang Xu, Rui-Xun Zhao, Kaitlin D Werle, Yong Wang, Xiao-Long Liu, Qiu Chen, Zhuo-Jun Wu, Ke Zhang, Ying Zhao, Guo-Qin Jiang, Feng-Mei Cui, Zhi-Xiang Xu
• Journal: Aging (Aging (Albany NY)) Vol. 12 Issue 14 Pg. 14341-14354 (07 16 2020) ISSN: 1945-4589 [Electronic] United States
• PMID: 32668413 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• BIRC5 protein, human
• RNA, Small Interfering
• Survivin
• Protein Serine-Threonine Kinases
• STK11 protein, human
• AMP-Activated Protein Kinase Kinases

Topics

• AMP-Activated Protein Kinase Kinases
• Cell Line, Tumor
• Centromere (drug effects)
• Chromosome Aberrations
• Genes, p53 (drug effects)
• Genome (drug effects)
• Humans
• Intestinal Polyps (genetics)
• Mitosis (drug effects)
• Peutz-Jeghers Syndrome (genetics)
• Protein Serine-Threonine Kinases (antagonists & inhibitors, genetics)
• RNA, Small Interfering (biosynthesis, genetics)
• Survivin (biosynthesis, genetics)
• Tumor Stem Cell Assay
• Up-Regulation (genetics)