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. Zhang; Y.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

doi:10.1126/scitranslmed.aad6066

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

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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 language	English
Pages (from-to)	350ra104
Journal	Science Translational Medicine
Volume	8
Issue number	350
DOIs	https://doi.org/10.1126/scitranslmed.aad6066
Publication status	Published - 3 Aug 2016

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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 CEBPa expression. Science Translational Medicine, 8(350), 350ra104. https://doi.org/10.1126/scitranslmed.aad6066

@article{ac8e327774d44860b6e3f8087b37edc7,

title = "Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPa expression",

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.",

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

year = "2016",

month = aug,

day = "3",

doi = "10.1126/scitranslmed.aad6066",

language = "English",

volume = "8",

pages = "350ra104",

journal = "Science Translational Medicine",

issn = "1946-6234",

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number = "350",

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Yong, KJ, Basseres, DS, Welner, RS, Zhang, WC, Yang, H, Yan, B, Alberich-Jorda, M, Zhang, J, De Figueiredo-Pontes, LL, Battelli, C, Hetherington, CJ, Ye, M, Zhang, H, Maroni, G, O'Brien, K, Magli, MC, Borczuk, AC, Varticovski, L, Kocher, O, Zhang, P, Moon, YC, Sydorenko, N, Cao, L, Davis, TW, Thakkar, BM, Soo, RA, Iwama, A, Lim, B, Halmos, B, Neuberg, D, Tenen, DG & Levantini, E 2016, 'Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPa expression', Science Translational Medicine, vol. 8, no. 350, pp. 350ra104. https://doi.org/10.1126/scitranslmed.aad6066

TY - JOUR

T1 - Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPa expression

AU - Yong, K.J.

AU - Basseres, D.S.

AU - Welner, R.S.

AU - Zhang, W.C.

AU - Yang, H.

AU - Yan, B.

AU - Alberich-Jorda, M.

AU - Zhang, J.

AU - De Figueiredo-Pontes, L.L.

AU - Battelli, C.

AU - Hetherington, C.J.

AU - Ye, M.

AU - Zhang, H.

AU - Maroni, G.

AU - O'Brien, K.

AU - Magli, M.C.

AU - Borczuk, A.C.

AU - Varticovski, L.

AU - Kocher, O.

AU - Zhang, P.

AU - Moon, Y.C.

AU - Sydorenko, N.

AU - Cao, L.

AU - Davis, T.W.

AU - Thakkar, B.M.

AU - Soo, Roland A.

AU - Iwama, A.

AU - Lim, B.

AU - Halmos, B.

AU - Neuberg, D.

AU - Tenen, D.G.

AU - Levantini, E.

PY - 2016/8/3

Y1 - 2016/8/3

N2 - 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.

AB - 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.

U2 - 10.1126/scitranslmed.aad6066

DO - 10.1126/scitranslmed.aad6066

M3 - Article

C2 - 27488898

SN - 1946-6234

VL - 8

SP - 350ra104

JO - Science Translational Medicine

JF - Science Translational Medicine

IS - 350

ER -

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

Abstract

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