Livin Regulates H2A.XY142 Phosphorylation and Promotes Autophagy in Colon Cancer Cells via a Novel Kinase Activity.

Objective: To investigate Livin-mediated regulation of H2A.XY142 phosphorylation via a novel kinase activity and its effect on autophagy in colon cancer cells. Methods: The interaction between Livin and H2A.X was tested by immunoprecipitation. H2A.X-/- HCT116 cells were transfected with human influenza hemagglutinin (HA)-tagged WT or Y142F phospho-dead mutantH2A.X plasmids. GST-tagged recombinant Livin protein was used to perform in vitro pull-down experiment and kinase assay. H2A.X-/-Livin+/+ SW480 cells were co-transfected with H2A.XWT/H2A.XY142F plasmid and LC3 EGFP-tagged plasmid to explore whether H2A.XY142F was involved in Livin-mediated autophagy induced by starvation in colon cancer cells. Results: Co-immunoprecipitation studies confirmed that Livin interacted with H2A.X and that it was phosphorylation dependent. In vitro kinase assay confirmed that Livin could phosphorylate H2A.X. Knockdown of Livin (Livin-/-) in SW480 cells or HCT116 cells canceled the starvation-induced autophagy in colon cancer cells; H2A.X-/-Livin+/+ SW480 cells transfected with H2A.XWT activated autophagy induced by starvation while cells transfected with H2A.XY142F had no significant difference; Livin-H2A.XY142F axis activated autophagy in colon cancer cells through transcriptionally regulating ATG5 and ATG7. Conclusion: Livin promotes autophagy in colon cancer cells via regulating the phosphorylation of H2A.XY142.

Association between GSTT1 Homozygous Deletion and Risk of Pancreatic Cancer: A Meta Analysis.

Objective To clarify the possible association of GSTT1 homozygous deletion with the susceptibility to pancreatic cancer. Methods We searched PubMed database, Chinese Journal Full Text Database (CNKI), and EMBASE to find the eligible studies published up to April 18, 2018 for evaluating the relationship between GSTT1 homozygous deletion and pancreatic cancer. The frequency of null genotype for GSTT1 between the pancreatic cancer group and the healthy control group was compared with Chi-square test, and odds ratios (ORs) value and 95% confidence interval (95% CI) were calculated. Results A total of 9 studies met the inclusion criteria, and 5952 cases consisting of 2387 pancreatic cancer patients and 3565 healthy controls were included in the meta analysis. Compared with the control group, frequency of null genotype for GSTT1 in the pancreatic cancer group was higher (33.4% vs. 38.7%, OR = 1.26, 95%CI = 1.01-1.58, P = 0.04). Conclusion GSTT1 homozygous deletion individuals may have higher susceptibility to pancreatic cancer.

Livin promotes colon cancer progression by regulation of H2A.XY39ph via JMJD6.

Livin is an important member of the human inhibitor of apoptosis proteins (IAPs) family. IAPs are proteins with antiapoptotic abilities, and their functions are different from the Bcl-2 (B-cell lymphoma-2) family proteins. However, the precise role of Livin in colon cancer progression remains unclear. The purpose of this study is to assess the effect of overexpression Livin in colon cancer cells and to examine its molecular mechanism. We demonstrated that Livin induced a colon cancer phenotype, including proliferation and migration, by regulating H2A.XY39ph (histone family 2A variant (H2AX) phosphorylated on the 39th serine site). We elucidated that Livin degraded Jumonji-C domain-containing 6 protein (JMJD6), which was mediated by the proteasome murine double minute 2 (MDM2), thereby regulating H2A.XY39ph. Above all, the overexpression of JMJD6 recovered H2A.XY39ph in colon cancer cells with a high level of Livin, thus inhibiting colon cancer malignancy progression. These results reveal a previously unrecognized role for Livin in regulating the tumor-initiating capacity in colon cancer and provide a novel treatment strategy in cancer via the interruption of H2A.XY39ph function and the interaction between H2A.XY39ph and JMJD6.

The prevalence and persistence of aberrant promoter DNA methylation in benzene-exposed Chinese workers.

Aberrant DNA methylation patterns are common in cancers and environmental pollutant exposed subjects. Up to date, few studies have examined the aberrant DNA methylation patterns in benzene exposed workers. We recruited 141 benzene-exposed workers, including 83 benzene-exposed workers from a shoe factory in Wenzhou and 58 workers from a painting workshop in Wuhu, 35 workers in Wuhu were followed from 2009 to 2013, and 48 indoor workers as controls from Wenzhou. We used high-resolution melting (HRM) to quantitate human samples of DNA methylation in long interspersed nuclear element-1 (LINE-1), (6)-methylguanine-DNA methyltransferase (MGMT), and DNA mismatch repair gene human mutator L homologue 1 (hMLH1). AML-5 cells were treated with benzoquinone (BQ) and hydroquinone (HQ), and the promoter methylation of MGMT and hMLH1 was detected using the bisulfite sequencing PCR method. The degree of LINE-1 methylation in benzene-exposed workers was significantly lower than that of the controls (p<0.001), and the degree of MGMT (p<0.001) and hMLH1 (p = 0.01) methylation was significantly higher than that of the controls. The in vitro study validated the aberrant hypermethylation of hMLH1 after treatment with BQ. Among the cohort workers who were followed from 2009 to 2013, the LINE1 methylation elevated in 2013 than 2009 (p = 0.004), and premotor methylation in hMLH1 reduced in 2013 than 2009 (p = 0.045) with the reduction of the benzene exposure. This study provides evidence that benzene exposure can induce LINE-1 hypomethylation and DNA repair gene hypermethylation.

MTHFR Gene Polymorphism Is Associated With DNA Hypomethylation and Genetic Damage Among Benzene-Exposed Workers in Southeast China.

OBJECTIVE AND METHODS: To analyze the association between global DNA methylation and single-nucleotide polymorphisms (SNPs) in methylenetetrahydrofolate reductase (MTHFR). MTHFR polymorphisms rs1801133 and rs1801131 were detected using the restriction fragment length polymorphism method, and cytokinesis-block micronucleus (MN) frequency and global DNA methylation was measured in workers from 410 shoe factories. RESULTS: A multilinear regression analysis demonstrated that DNA methylation of the TT variant allele of rs1801133 was lower than that of the CC wild type allele (Exp(ß) [95% CI], 0.76 [0.56, 1.02], P = 0.071), with a P-value approaching significance. A significantly increased MN frequency was observed for carriers of the TT genotype (frequency ratio = 1.27, 95% CI: 1.07-1.51, P < 0.01). CONCLUSION: The results imply that the TT genotype in rs1801133 is associated with global DNA hypomethylation, which may influence the induction of MN following exposure to benzene.