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

0473109 - ÚMG 2017 RIV US eng J - Journal Article
Yong, K.J. - Basseres, D.S. - Welner, R.S. - Zhang, W.C. - Yang, H. - Yan, B. - Alberich-Jorda, Meritxell - 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. - Zhang, P. - Moon, Y.C. - Sydorenko, N. - Cao, L. - Davis, T.W. - Thakkar, B.M. - Soo, R.A. - Iwama, A. - Lim, B. - Halmos, B. - Neuberg, D. - Tenen, D.G. - Levantini, E.
Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBP alpha expression.
Science Translational Medicine. Roč. 8, č. 350 (2016), č. článku 350ra104. ISSN 1946-6234. E-ISSN 1946-6242
R&D Projects: GA MŠMT LK21307
Institutional support: RVO:68378050
Keywords : ccaat/enhancer-binding-protein * acute myeloid-leukemia * factor-c/ebp-alpha * posttranscriptional control * adjuvant chemotherapy * cell-proliferation * down-regulation * drug discovery * gene signature * self-renewal
Subject RIV: EB - Genetics ; Molecular Biology
Impact factor: 16.761, year: 2016

Lung cancer is the most common cause of cancer deaths. The expression of the transcription factor C/EBP alpha (CCAAT/enhancer binding protein a) is frequently lost in non-small cell lung cancer, but the mechanisms by which C/EBP alpha suppresses tumor formation are not fully understood. In addition, no pharmacological therapy is available to specifically target C/EBP alpha expression. We discovered a subset of pulmonary adenocarcinoma patients in whom negative/low C/EBP alpha 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/EBP alpha deletion that develops lung adenocarcinomas, which are prevented by Bmi1 haploinsufficiency. BMI1 activity is required for both tumor initiation and maintenance in the C/EBP alpha-null background, and pharmacological inhibition of BMI1 exhibits antitumor effects in both murine and human adenocarcinoma lines. Overall, we show that C/EBP alpha is a tumor suppressor in lung cancer and that BMI1 is required for the oncogenic process downstream of C/EBP alpha loss. Therefore, anti-BMI1 pharmacological inhibition may offer a therapeutic benefit for lung cancer patients with low expression of C/EBP alpha and high BMI1.
Permanent Link: http://hdl.handle.net/11104/0270322