Background: Notch-1 plays a critical role in cell fate decisions by modulating cellular processes under irradiation. Results: Irradiation-induced Notch-1 overexpression promoted survival and EMT in NSCLC, whereas rhamnetin and cirsiliol inhibited these effects via miR-34a-mediated Notch-1 down-regulation. Conclusion: Rhamnetin and cirsiliol suppress Notch-1-mediated radioresistance and EMT phenotypes in NSCLC. Significance: Rhamnetin and cirsiliol can act as novel radiosensitizers by inhibiting radiation-induced Notch-1 signaling.

Frequent relapse and spreading of tumors during radiotherapy are principal obstacles to treatment of non-small cell lung cancer (NSCLC). In this study, we aimed to investigate how macrophage migration inhibitory factor (MIF) which is expressed at high levels in metastatic and primary lung cancer cells could regulate NSCLC metastasis in response to ionizing radiation (IR). The results indicated that MIF and ribosomal protein S3 (rpS3) were shown to be connected to inflammation, proliferation, and metastasis of NSCLC via IR-induced activation of the NF-κB pathway. Under unirradiated conditions, MIF physically established a complex with rpS3. MIF-rpS3 dissociation induced by IR activated NF-κB and made the expression of target genes of this factor transactivated in two NSCLC cell lines, A549, and NCI-H358. We also found that IR-induced dissociation of this complex led to increased secretion of pro-inflammatory cytokines and modulated the expression of epithelial-mesenchymal transition marker proteins. Finally, the effects of IR-induced dissociation of the MIF-rpS3 complex on tumor metastasis were confirmed by in vivo xenograft studies. Taken together, the present study revealed that dissociation of the MIF-rpS3 complex and subsequent activation of NF-κB is a critical post-IR exposure event that accounts for IR-induced metastatic conversion of NSCLC.

Although ASXL1 mutations are frequently found in human diseases, including myeloid leukemia, the cell proliferation-associated function of ASXL1 is largely unknown. Here, we explored the molecular mechanism underlying the growth defect found in Asxl1-deficient mouse embryonic fibroblasts (MEFs). We found that Asxl1, through amino acids 371 to 655, interacts with the kinase domain of AKT1. In Asxl1-null MEFs, IGF-1 was unable to induce AKT1 phosphorylation and activation; p27Kip1, which forms a ternary complex with ASXL1 and AKT1, therefore remained unphosphorylated. Hypophosphorylated p27Kip1 is able to enter the nucleus, where it prevents the phosphorylation of Rb; this ultimately leads to the down-regulation of E2F target genes as confirmed by microarray analysis. We also found that senescence-associated (SA) genes were upregulated and that SA β-gal staining was increased in Asxl1 −/− MEFs. Further, the treatment of an AKT inhibitor not only stimulated nuclear accumulation of p27Kip1 leading to E2F inactivation, but also promoted senescence. Finally, Asxl1 disruption augmented the expression of p16Ink4a as result of the defect in Asxl1-Ezh2 cooperation. Overall, our study provides the first evidence that Asxl1 both activates the AKT-E2F pathway and cooperates with Ezh2 through direct interactions at early embryonic stages, reflecting that Asxl1 disruption causes cellular senescence.The additional sex comb (Asx) gene was originally identified in Drosophila as an enhancer of trithorax group (TrxG) and Polycomb group (PcG) proteins 1 . Three paralog Asx-like (Asxl) genes have been found in mammals, encoding ASXL1, ASXL2, and ASXL3 2-4 . We recently reported that ASXL1 is mainly located in the nucleus and acts as a dual-function regulator of nuclear receptors, either cooperating with SRC1 for activation or with HP1 for repression in the presence of a ligand 5,6 . ASXL1 also seems to function as a tumor suppressor. Mutations of ASXL1 are often found in human diseases and are mostly linked to acute myeloid leukemia 7 , myelodysplastic syndromes and chronic myelomonocytic leukemia 8 , and Bohring-Opitz syndrome 9 . Despite the somatic ASXL1 mutations frequently reported in leukemia patients, the mechanisms by which ASXL1 mutations cause cancer are not fully understood. Recent studies using leukemia cells from human patients with ASXL1 mutations showed that ASXL1 interacts with histone methyltransferase EZH2, one of PRC2 members, to increase histone H3K27 tri-methylation (me3) 10 . In addition, Asxl1 deletion in mice was accompanied with reduction of H3K27me3. In contrast, loss of Bap1, one of Asxl1 binding partners, resulted in enhanced H3K27me3 level and EZH2-dependent transformation 11 , suggesting distinct, independent roles of Asxl1 and Bap1 in myeloid leukemogenesis.AKT, also called protein kinase B, was identified as the cellular counterpart of a viral oncogene. Amplified AKT isoforms has been found in several types of human cancers [12][13][14] . Not only is AKT a key regulator of cell

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