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, Hong Zhang, Giorgia Maroni, Karen O'Brien, Maria Cristina Magli, Alain C. Borczuk, Lyuba Varticovski, Olivier Kocher, Pu ZhangYoung Choon Moon, Nadiya Sydorenko, Liangxian Cao, Thomas W. Davis, Bhavin M. Thakkar, Ross A. Soo, Atsushi Iwama, Bing Lim, Balazs Halmos, Donna Neuberg, Daniel G. Tenen, Elena Levantini

Research output: Contribution to journalArticle

26 Scopus citations

Abstract

Lung cancer is the most common cause of cancer deaths. The expression of the transcription factor C/EBPα (CCAAT/enhancer binding protein a) 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.

Original languageEnglish (US)
Pages (from-to)350ra104
JournalScience Translational Medicine
Volume8
Issue number350
DOIs
StatePublished - Aug 3 2016

ASJC Scopus subject areas

  • Medicine(all)

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    Yong, K. J., Basseres, D. S., Welner, R. S., Zhang, W. C., Yang, H., Yan, B., Alberich-Jorda, M., Zhang, J., De Figueiredo-Pontes, L. L., Battelli, C., Hetherington, C. J., Ye, M., Zhang, H., Maroni, G., O'Brien, K., Magli, M. C., Borczuk, A. C., Varticovski, L., Kocher, O., ... Levantini, E. (2016). Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPα expression. Science Translational Medicine, 8(350), 350ra104. https://doi.org/10.1126/scitranslmed.aad6066