Lung cancer is the most common cause of cancer deaths. The expression of the transcription factor C/EBPα (CCAAT/enhancer binding protein α) is frequently lost in non-small cell lung cancer, but the mechanisms by which C/EBPα suppresses tumor formation are not fully understood. In addition, no pharmacological therapy is available to specifically target C/EBPα expression. We discovered a subset of pulmonary adenocarcinoma patients in whom negative/low C/EBPα expression and positive expression of the oncogenic protein BMI1 (B lymphoma Mo-MLV insertion region 1 homolog) have prognostic value. We also generated a lung-specific mouse model of C/EBPα deletion that develops lung adenocarcinomas, which are prevented by Bmi1 haploinsufficiency. BMI1 activity is required for both tumor initiation and maintenance in the C/EBPα-null background, and pharmacological inhibition of BMI1 exhibits antitumor effects in both murine and human adenocarcinoma lines. Overall, we show that C/EBPα is a tumor suppressor in lung cancer and that BMI1 is required for the oncogenic process downstream of C/EBPα loss. Therefore, anti-BMI1 pharmacological inhibition may offer a therapeutic benefit for lung cancer patients with low expression of C/EBPα and high BMI1.

• MeSH
• Adenocarcinoma genetics   metabolism   pathology   therapy   MeSH
• Humans MeSH
• Mutation genetics   MeSH
• Mice, Knockout MeSH
• Mice MeSH
• Lung Neoplasms genetics   metabolism   pathology   therapy   MeSH
• Polycomb Repressive Complex 1 genetics   metabolism   MeSH
• CCAAT-Enhancer-Binding Protein-alpha genetics   metabolism   MeSH
• Proto-Oncogene Proteins genetics   metabolism   MeSH
• Gene Expression Regulation, Neoplastic genetics   MeSH
• Animals MeSH
• Check Tag
• Humans MeSH
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH
• Research Support, N.I.H., Extramural MeSH

BACKGROUND INFORMATION: The optimal repair of DNA lesions is fundamental for physiological processes. We asked whether the recruitment of HP1β, 53BP1 and BMI1 proteins to ultraviolet (UVA)-induced DNA lesions requires functional A-type lamins. RESULTS: We found that UVA irradiation of nuclear lamina abolished the fluorescence of mCherry-tagged A-type lamins and destroyed the nuclear lamina as also observed by electron microscopy studies. Similarly, an absence of endogenous A- and B-type lamins was found in irradiated regions by UVA. However, irradiation did not affect the recruitment of HP1β, 53BP1 and BMI1 to DNA lesions. The UVA-induced shrinkage of the nuclear lamina, which anchors chromatin, explains why UVA-micro-irradiated chromatin is relaxed. Conversely, additional experiments with γ-irradiation showed that the nuclear lamina remained intact and the genome-wide level of HP1β was stable. Fluorescence intensity of HP1β and BMI1 in UVA-induced DNA lesions and level of HP1β after γ-irradiation were unaffected by deficiency in A-type lamins, whereas those parameters of 53BP1 were changed. CONCLUSIONS: We conclude that only the 53BP1 status in DNA lesions, induced by UVA or γ-rays, is affected by A-type lamin deficiency, which was not observed for heterochromatin-related proteins HP1β and BMI1.

• MeSH
• 3T3 Cells MeSH
• Chromosomal Proteins, Non-Histone analysis   metabolism   MeSH
• DNA-Binding Proteins analysis   metabolism   MeSH
• DNA genetics   MeSH
• Lamin Type A analysis   metabolism   MeSH
• Mice MeSH
• DNA Damage radiation effects   MeSH
• Polycomb Repressive Complex 1 analysis   metabolism   MeSH
• Proto-Oncogene Proteins analysis   metabolism   MeSH
• Ultraviolet Rays MeSH
• Animals MeSH
• Check Tag
• Mice MeSH
• Animals MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH

BACKGROUND INFORMATION: A Polycomb (PcG) body is an orphan nuclear subcompartment characterised by accumulations of Polycomb repressive complex 1 (PRC1) proteins. However, seemingly contradictory reports have appeared that describe the PcG bodies either as protein-based bodies in the interchromatin compartment or chromatin domains. In this respect, molecular crowding is an important factor for the assembly and stability of nuclear subcompartments. In order to settle this contradiction, crowding experiments, that represent a convenient model distinguishing between interchromatin and chromatin compartments, were carried out. RESULTS: In sucrose-hypertonically induced crowding, we observed in U-2 OS cells that PcG bodies disappeared, but persisted as nuclear domains characterised by accumulations of DNA. This phenomenon was also observed in cells hypertonically treated with sorbitol and NaCl. Importantly, the observed changes were quickly reversible after re-incubation of cells in normal medium. We found that the PcG foci disappearance and the dissociation of PRC1 proteins (BMI1 and RING1a proteins) from chromatin were associated with their hyper-phosphorylation. In addition, under hyper- and hypotonic conditions, the behaviour of the PcG bodies differed from that of the typical nucleoplasmic body. CONCLUSION: PRC1 proteins accumulations do not represent a genuine nuclear subcompartment. The PcG body is a chromosomal domain, rather than a nucleoplasmic body.

• MeSH
• Anthraquinones metabolism   MeSH
• Staining and Labeling MeSH
• Chromatin metabolism   MeSH
• Fluorescence MeSH
• Phosphorylation drug effects   MeSH
• Transcription, Genetic drug effects   MeSH
• Hypertonic Solutions pharmacology   MeSH
• Humans MeSH
• Macromolecular Substances metabolism   MeSH
• Cell Line, Tumor MeSH
• Polycomb-Group Proteins metabolism   MeSH
• Polycomb Repressive Complex 1 metabolism   MeSH
• RNA genetics   metabolism   MeSH
• Sucrose pharmacology   MeSH
• Check Tag
• Humans MeSH
• Publication type
• Journal Article MeSH
• Research Support, Non-U.S. Gov't MeSH