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

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

SUBMITTER: Yong KJ

PROVIDER: S-EPMC8214331 | biostudies-literature | 2016 Aug

REPOSITORIES: biostudies-literature

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

Yong Kol Jia KJ Basseres Daniela S DS Welner Robert S RS Zhang Wen Cai WC Yang Henry H Yan Benedict B Alberich-Jorda Meritxell M Zhang Junyan J de Figueiredo-Pontes Lorena Lobo LL Battelli Chiara C Hetherington Christopher J CJ Ye Min M Zhang Hong H Maroni Giorgia G O'Brien Karen K Magli Maria Cristina MC Borczuk Alain C AC Varticovski Lyuba L Kocher Olivier O Zhang Pu P Moon Young-Choon YC Sydorenko Nadiya N Cao Liangxian L Davis Thomas W TW Thakkar Bhavin M BM Soo Ross A RA Iwama Atsushi A Lim Bing B Halmos Balazs B Neuberg Donna D Tenen Daniel G DG Levantini Elena E

Science translational medicine 20160801 350

Lung cancer is the most common cause of cancer deaths. The expression of the transcription factor C/EBPα (CCAAT/enhancer binding protein α) 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 t ...[more]

PMID: 27488898

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Project description:BackgroundBmi1 (B lymphoma Mo-MLV insertion region 1 homolog) contributes to human tumorigenesis via epigenetic transcriptional silencing and represents a novel therapeutic target with great potentials. Here we sought to determine the therapeutic efficiency of PTC-209, a potent and selective Bmi1 inhibitor, in head neck squamous cell carcinoma (HNSCC) cells and a HNSCC xenograft model.MethodsThe mutation pattern, mRNA level of Bmi1 in HNSCC and its associations with clinicopathological parameters were determined through comprehensive data mining and interrogation using publicly available databases GENT, cBioPortal, Oncomine and TCGA. The PTC-209, a selective and potent Bmi1 inhibitor, was exploited and its effect on Bmi1 expression was measured in two HNSCC cell lines Cal27 and FaDu. The phenotypical changes of HNSCC cells were observed upon PTC-209 treatment in vitro. Moreover, the therapeutic effects of PTC-209 for HNSCC were determined in a xenograft animal model.ResultsThrough comprehensive data mining and interrogation, we found that Bmi1 mRNA was frequently overexpressed in a subset of HNSCC samples. Our data revealed that PTC-209 robustly reduced the expression of Bmi1 in Cal27 and FaDu cells presumably by post-transcriptional repression and ubiquitin-proteasomal degradation. PTC-209 treatment resulted in impaired cell proliferation, G1-phase cell cycle arrest, compromised migration and invasiveness, and increased cell apoptosis and chemosensitivity to 5-FU and cisplatin in vitro. Moreover, PTC-209 exposure reduced colony formation, tumorsphere formation and the percentage of ALDH1+ subpopulation in both Cal27 and FaDu cells. Importantly, in vivo PTC-209 administration significantly reduced tumor growth in a HNSCC xenograft model probably by Bmi1 inhibition and impaired cell proliferation.ConclusionsOur findings indicate that pharmacological inhibition of Bmi1 is a novel therapeutic strategy for HNSCC patients, especially with those with aberrant Bmi1 overexpression.

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

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

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