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

K.J. Yong, D.S. Basseres, R.S. Welner, W.C. Zhang, H. Yang, B. Yan, M. Alberich-Jorda, J. Zhang, L.L. De Figueiredo-Pontes, C. Battelli, C.J. Hetherington, M. Ye, H. Zhang, G. Maroni, K. O'Brien, M.C. Magli, A.C. Borczuk, L. Varticovski, O. Kocher, P. ZhangY.C. Moon, N. Sydorenko, L. Cao, T.W. Davis, B.M. Thakkar, Roland A. Soo, A. Iwama, B. Lim, B. Halmos, D. Neuberg, D.G. Tenen, E. Levantini

    Research output: Contribution to journalArticle

    33 Citations (Scopus)

    Abstract

    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 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.
    Original languageEnglish
    Pages (from-to)350ra104
    JournalScience Translational Medicine
    Volume8
    Issue number350
    DOIs
    Publication statusPublished - 2016

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