High-risk human papillomaviruses (HPVs) are causative agents of anogenital cancers and a fraction of head and neck cancers. The mechanisms involved in the progression of HPV neoplasias to cancers remain largely unknown. Here, we report that O-linked GlcNAcylation (O-GlcNAc) and O-GlcNAc transferase (OGT) were markedly increased in HPV-caused cervical neoplasms relative to normal cervix, whereas O-GlcNAcase (OGA) levels were not altered. Transduction of HPV16 oncogene E6 or E6/E7 into mouse embryonic fibroblasts (MEFs) up-regulated OGT mRNA and protein, elevated the level of O-GlcNAc, and promoted cell proliferation while reducing cellular senescence. Two HR HPV genes, E6 and E7, are potent oncogenes based on their immortalizing and transforming activities in cell culture systems and their capacities to induce tumors in animal models. The HR HPV E7 oncoprotein binds to more than 20 cellular targets and interferes with multiple cellular processes, leading to deregulated cell cycle, centrosome amplification, DNA damage, anoikis resistance, anchorage-independent cell growth and malignant transformation as well as immune surveillance evasion.

Activation of AMPK protects against necroptosis via promoting Keap1-mediated PGAM5 degradation. Metformin may act as a valuable agent for the protection of myocardial ischemia and reperfusion injury by activating AMPK and reducing necroptosis.

Liver kinase B1 (LKB1) functions as a tumor suppressor encoded by STK11, a gene that mutated in Peutz-Jeghers syndrome and in sporadic cancers. Previous studies showed that LKB1 participates in IR- and ROS-induced DNA damage response (DDR). However, the impact of LKB1 mutations on targeted cancer therapy remains unknown. Herein, we demonstrated that LKB1 formed DNA damage-induced nuclear foci and co-localized with ataxia telangiectasia mutated kinase (ATM), γ-H2AX, and breast cancer susceptibility 1 (BRCA1). ATM mediated LKB1 phosphorylation at Thr 363 following the exposure of cells to ionizing radiation (IR). LKB1 interacted with BRCA1, a downstream effector in DDR that is recruited to sites of DNA damage and functions directly in homologous recombination (HR) DNA repair. LKB1 deficient cells exhibited delayed DNA repair due to insufficient HR. Notably, LKB1 deficiency sensitized cells to poly (ADP-ribose) polymerase (PARP) inhibitors. Thus, we have demonstrated a novel function of LKB1 in DNA damage response. Cancer cells lacking LKB1 are more susceptible to DNA damage-based therapy and, in particular, to drugs that further impair DNA repair, such as PARP inhibitors.

Background: Treatment of Crohn's disease (CD) remains to be a challenge due to limited insights for its pathogenesis. We aimed to determine the role of O-Linked b-N-acetylglucosamine (O-GlcNAc) in the development of CD and evaluate therapeutic effects of O-GlcNAc inhibitors on CD. Methods: O-GlcNAc in intestinal epithelial tissues of CD, adherent-invasive Escherichia coli (AIEC) LF82infected cells and mice was determined by immunoblot and immunohistochemistry. AIEC LF82 and dextran sulfate sodium were administrated into C57BL/6 mice for estabolishing inflammatory bowel disease model and for therapeutic study. Findings: O-GlcNAc was increased in intestinal epithelial tissues of CD patients and AIEC LF82-infected mice. Infection of AIEC LF82 up-regulated the level of UDP-GlcNAc and increased O-GlcNAc in human colon epithelial HCT116 and HT-29 cells. We identified that IKKb and NF-kB were O-Glycosylated in AIEC LF82-treated cells. Mutations of IKKb (S733A) and p65 (T352A) abrogated the O-GlcNAc in IKKb and NF-kB and inhibited AIEC LF82-induced activation of NF-kB. Application of 6-diazO-5-oxO-L-norleucine, an agent that blocks the production of UDP-GlcNAc and inhibits O-GlcNAc, inactivated NF-kB in AIEC LF82-infected cells, enhanced the formation of autophagy, promoted the removal of cell-associated AIEC LF82, alleviated intestinal epithelial inflammation, and improved the survival of the colitis mice. Interpretation: Intestinal inflammation in CD is associated with increased O-GlcNAc modification, which is required for NF-kB activation and suppression of autophagy. Targeting O-GlcNAc could be an effective therapy for inflammatory bowel disease.

Background Ulcerative colitis (UC) is a chronic inflammatory disease whose therapy remains largely uncertain due to the lack of etiological understanding. It is also a higher risk factor for colon cancer. Aims This study was designed to identify key genes correlated with intestinal epithelial repair and their associated signaling pathways in the pathogenesis and malignant transformation of UC.Methods With an online database pubmed2ensemble, correlative genes were identified to be associated with both UC and its self-healing, and then were imported in Cytoscape for enrichment analysis. A protein-protein interaction network containing was established, and the most significant gene modules and top ten hub genes were selected for further enrichment analysis. Then, potential drugs that target the corresponding genes were identified with online tool in DGIdb. A map which reflected the links among genes, drugs, and their associated pathways was constructed. Finally, we searched the TCGA database and CPTAC database for testing the gene expression of identified UC-associated genes in colon cancer.Results We identified FN1, GRB2, EGF, CXCL8, VEGFA, STAT3, IL6, IL4, IL10, TNF, CSF2, IL13, IL1A, CCL2, ICAM1 and IL18 had closest associations with the function of epithelial function in UC patients, based on functional enrichment analysis. Besides, 11 of them were validated in colon cancer. Conclusions The corresponding signaling pathways that are altered in UC, which provide a new clue for understanding the mechanism underlying the UC pathogenesis and malignant transformation. Key signals in the process and their target drugs might serve as new treatment strategy for UC.