State Key Laboratory of Radiation Medicine and Protection, School of Radiation Medicine and Protection, Soochow University, Suzhou 215123, China.
Department of General Surgery, The Second Affiliated Hospital, Soochow University, Suzhou 215004, China.
Aging (Albany NY). 2020 Jul 16;12(14):14341-14354. doi: 10.18632/aging.103473.
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.
肝激酶 B1（LKB1）肿瘤抑制基因的失活突变是 Peutz-Jeghers 综合征（PJS）的基础，并且经常发生在各种人类癌症中。我们之前表明，LKB1 通过 PLK1 调节中心体复制。在这里，我们报告 LKB1 通过负调控染色体乘客复合物（CPC）的成员 survivin 进一步有助于维持基因组稳定性，该复合物介导 CPC 向着丝粒的靶向。我们发现 LKB1 的缺失导致中期和后期染色体的错位和滞后积累，并增加多核和微核细胞的出现。异位 LKB1 表达减少了这些特征，并改善了 LKB1 缺陷细胞的有丝分裂保真度。通过药理学和遗传操作，我们表明 LKB1 介导的 survivin 抑制不依赖于 AMPK，但需要 p53。与 LKB1 对 survivin 表达的关键影响一致，免疫组织化学分析表明 PJS 患者的肠息肉中高表达 survivin。最后，我们通过证明 LKB1 缺陷细胞对 survivin 抑制剂的敏感性增加，再次证实了治疗 LKB1 突变肿瘤的潜在治疗途径。
