In the advanced stages of cancer, autophagy is thought to promote tumor progression through its ability to mitigate various cellular stresses. However, the details of how autophagy is homeostatically regulated in such tumors are unknown. Here, we report that NUPR1 (nuclear protein 1, transcriptional regulator), a transcriptional coregulator, is aberrantly expressed in a subset of cancer cells and predicts low overall survival rates for lung cancer patients. NUPR1 regulates the late stages of autolysosome processing through the induction of the SNARE protein SNAP25, which forms a complex with the lysosomal SNARE-associated protein VAMP8. NUPR1 depletion deregulates autophagic flux and impairs autolysosomal clearance, inducing massive cytoplasmic vacuolization and premature senescence in vitro and tumor suppression in vivo. Collectively, our data show that NUPR1 is a potent regulator of autolysosomal dynamics and is required for the progression of some epithelial cancers.

Genome wide association studies (GWAS) have shown that SNPs in non-coding regions are associated with inherited susceptibility to cancer. The effect of one single SNP, however, is weak. To identify potential co-factors of SNPs, we investigated the underlying mechanism by which SNPs affect lung cancer susceptibility. We found that rs2853677 is located within the Snail1 binding site in a TERT enhancer. This enhancer increases TERT transcription when juxtaposed to the TERT promoter. The binding of Snail1 to the enhancer disrupts enhancer-promoter colocalization and silences TERT transcription. The high risk variant of rs2853677 disrupts the Snail1 binding site and derepresses TERT expression in response to Snail1 upregulation, thus increasing lung adenocarcinoma susceptibility. Our data suggest that Snail1 may be a co-factor of rs2853677 for predicting lung adenocarcinoma susceptibility and prognosis.

Ikaros, encoded by the IKZF1 gene, is a pivotal transcription factor whose expression and utilization is dynamically altered during hematopoietic development. However, the molecular mechanisms controlling the transcription of the IKZF1 gene are unclear in lung cancer cell lines. Here we show the role of Ikaros in a cohort of grade IIIA lung cancer patients, with particular emphasis on its relationship with clinical outcomes and expression levels. The expression levels of Ikaros were positively correlated with the prognosis in the lung cancer patients. We also demonstrated that Ikaros expression is ectopically activated in a panel of lung cancer cell lines primarily through demethylation of its promoter. Moreover, gain-offunction experiments revealed that Ikaros inhibits migration and invasion of lung cancer cells in vitro. Our results thus shed light on how Ikaros can act as a lineage competency factor to facilitate lung cancer progression. Anat Rec, 296:907-913, 2013

Lung adenocarcinoma (LUAD) has been considered as the most common cause of cancer-associated mortality. Radiotherapy resistance is one of the main reasons for LUAD treatment failure. The microRNA (miR)-101-3p has been previously reported to function as a tumor suppressor in several types of cancer, including LUAD. The present study aimed to explore the role and mechanism of miR-101-3p on radioresistance of lung adenocarcinoma cells through bioinformatics analysis and biological experiments. Based on the analysis of Gene Expression Omnibus (GEO) and The Cancer Genome Atlas (TCGA) data, it was demonstrated that the expression of miR-101-3p was low in LUAD tissues compared with normal lung tissues and was associated with poor prognosis of patients with LUAD. The results of the CCK-8 assay, colony formation assay, immunofluorescence staining, caspase-3 activity assay and western blotting demonstrated that miR-101-3p overexpression sensitized LUAD cells to ionizing radiation by decreasing the abilities of LUAD cell proliferation, colony formation, DNA damage repair and increasing caspase-3 activity and apoptosis of LUAD cells following ionizing radiation. Furthermore, according to bioinformatics analysis and luciferase assay, baculoviral IAP repeat containing 5 (BIRC5) was identified as a direct target of miR-101-3p. Increased BIRC5 expression reversed the miR-101-3p-mediated increase in LUAD cell radiotherapy sensitivity. Taken together, the results of the present study demonstrated that miR-101-3p may be considered as a potential target that can enhance LUAD cell sensitivity to radiotherapy, which may provide a new strategy to improve therapy in patients with LUAD.

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