TY - JOUR
T1 - Targeted BMI1 inhibition impairs tumor growth in lung adenocarcinomas with low CEBPα expression
AU - Yong, Kol Jia
AU - Basseres, Daniela S.
AU - Welner, Robert S.
AU - Zhang, Wen Cai
AU - Yang, Henry
AU - Yan, Benedict
AU - Alberich-Jorda, Meritxell
AU - Zhang, Junyan
AU - De Figueiredo-Pontes, Lorena Lobo
AU - Battelli, Chiara
AU - Hetherington, Christopher J.
AU - Ye, Min
AU - Zhang, Hong
AU - Maroni, Giorgia
AU - O'Brien, Karen
AU - Magli, Maria Cristina
AU - Borczuk, Alain C.
AU - Varticovski, Lyuba
AU - Kocher, Olivier
AU - Zhang, Pu
AU - Moon, Young Choon
AU - Sydorenko, Nadiya
AU - Cao, Liangxian
AU - Davis, Thomas W.
AU - Thakkar, Bhavin M.
AU - Soo, Ross A.
AU - Iwama, Atsushi
AU - Lim, Bing
AU - Halmos, Balazs
AU - Neuberg, Donna
AU - Tenen, Daniel G.
AU - Levantini, Elena
N1 - Funding Information:
This work was funded by NIH/NCI (National Cancer Institute) P50 CA90578 Project 2 grant (to D.G.T. and B.H.); the NCIS (National University Cancer Institute of Singapore) Yong Siew Yoon Research grant through donations from the Yong Loo Lin Trust, the Singapore Ministry of Health's National Medical Research Council under its Singapore Translational Research (STaR) Investigator Award, and the National Research Foundation of Singapore and the Singapore Ministry of Education under its Research Centres of Excellence initiative and PO1 CA66996 Project 3 and 1R35CA197697 grants (to D.G.T.); FAMRI (Flight Attendant Medical Research Institute) YCSA (Young Clinical Scientist Award) 052409 and FAMRI CIA (Clinical Innovator Awards) 103063 (to E.L.); FAMRI YCSA 072165 (to D.S.B.); Doctors Cancer Foundation Award (to E.L.); IASLC (International Association for the Study of Lung Cancer) Award (to E.L.); MIUR (Ministry of Education, University and Research) Flagship InterOmics Project (to E.L. and M.C.M.); and MSMT Navrat grant LK21307 (to M.-A.J.). R.S.W. was supported by a José Carreras fellowship, FIJC-10. C.B. was supported by an NCI T32/K12/R25 award. W.C.Z. and B.L.'s work was supported by Agency for Science, Technology and Research (AßSTAR), Singapore. R.A.S. was supported by the National Medical Research Council of Singapore (NMRC/CG/NCIS/2010). D.N. was supported by Dana-Farber/Harvard Cancer Center support grant 5P30 CA006516.
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/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.
AB - 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.
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UR - http://www.scopus.com/inward/citedby.url?scp=84982795836&partnerID=8YFLogxK
U2 - 10.1126/scitranslmed.aad6066
DO - 10.1126/scitranslmed.aad6066
M3 - Article
C2 - 27488898
AN - SCOPUS:84982795836
SN - 1946-6234
VL - 8
SP - 350ra104
JO - Science translational medicine
JF - Science translational medicine
IS - 350
ER -
