RESUMO
Cancer cells are often aneuploid and frequently display elevated rates of chromosome missegregation in a phenomenon called chromosomal instability (CIN). CIN is commonly caused by hyperstable kinetochore-microtubule (K-MT) attachments that reduces the efficiency of correction of erroneous K-MT attachments. We recently showed that UMK57, a chemical agonist of MCAK (alias KIF2C) improves chromosome segregation fidelity in CIN cancer cells although cells rapidly develop adaptive resistance. To determine the mechanism of resistance we performed unbiased proteomic screens which revealed increased phosphorylation in cells adapted to UMK57 at two Aurora kinase A phosphoacceptor sites on BOD1L1 (alias FAM44A). BOD1L1 depletion or Aurora kinase A inhibition eliminated resistance to UMK57 in CIN cancer cells. BOD1L1 localizes to spindles/kinetochores during mitosis, interacts with the PP2A phosphatase, and regulates phosphorylation levels of kinetochore proteins, chromosome alignment, mitotic progression and fidelity. Moreover, the BOD1L1 gene is mutated in a subset of human cancers, and BOD1L1 depletion reduces cell growth in combination with clinically relevant doses of taxol or Aurora kinase A inhibitor. Thus, an Aurora kinase A -BOD1L1-PP2A axis promotes faithful chromosome segregation during mitosis.
RESUMO
Background: Gastric adenocarcinomas are a leading cause of global mortality, associated with chronic infection with Helicobacter pylori. The mechanisms by which infection with H. pylori contributes to carcinogenesis are not well understood. Recent studies from subjects with and without gastric cancer have identified significant DNA methylation alterations in normal gastric mucosa associated with H. pylori infection and gastric cancer risk. Here we further investigated DNA methylation alterations in normal gastric mucosa in gastric cancer cases (n = 42) and control subjects (n = 42) with H. pylori infection data. We assessed tissue cell type composition, DNA methylation alterations within cell populations, epigenetic aging, and repetitive element methylation. Results: In normal gastric mucosa of both gastric cancer cases and control subjects, we observed increased epigenetic age acceleration associated with H. pylori infection. We also observed an increased mitotic tick rate associated with H. pylori infection in both gastric cancer cases and controls. Significant differences in immune cell populations associated with H. pylori infection in normal tissue from cancer cases and controls were identified using DNA methylation cell type deconvolution. We also found natural killer cell-specific methylation alterations in normal mucosa from gastric cancer patients with H. pylori infection. Conclusions: Our findings from normal gastric mucosa provide insight into underlying cellular composition and epigenetic aspects of H. pylori associated gastric cancer etiology.