Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPα expression

Kol Jia Yong, Daniela S. Basseres, Robert S. Welner, Wen Cai Zhang, Henry Yang, Benedict Yan, Meritxell Alberich-Jorda, Junyan Zhang, Lorena Lobo de Figueiredo-Pontes, Chiara Battelli, Christopher J. Hetherington, Min Ye (+20 others)
2016 Science Translational Medicine  
Lung cancer is the most common cause of cancer deaths. The expression of the transcription factor C/EBPa (CCAAT/ enhancer binding protein a) is frequently lost in non-small cell lung cancer, but the mechanisms by which C/EBPa suppresses tumor formation are not fully understood. In addition, no pharmacological therapy is available to specifically target C/EBPa expression. We discovered a subset of pulmonary adenocarcinoma patients in whom negative/low C/EBPa expression and positive expression of
more » ... 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/EBPa deletion that develops lung adenocarcinomas, which are prevented by Bmi1 haploinsufficiency. BMI1 activity is required for both tumor initiation and maintenance in the C/EBPa-null background, and pharmacological inhibition of BMI1 exhibits antitumor effects in both murine and human adenocarcinoma lines. Overall, we show that C/EBPa is a tumor suppressor in lung cancer and that BMI1 is required for the oncogenic process downstream of C/EBPa loss. Therefore, anti-BMI1 pharmacological inhibition may offer a therapeutic benefit for lung cancer patients with low expression of C/EBPa and high BMI1.
doi:10.1126/scitranslmed.aad6066 pmid:27488898 fatcat:pjz4j6flfjd3rdo5ktlywdmeo4