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

Yong, Kol Jia; Bassères, Daniela S.; Welner, Robert S.; Zhang, Wen Cai; Yang, Henry; Yan, Benedict; Alberich-Jordà, Meritxell; Zhang, Junyan; Figueiredo-Pontes, Lorena Lôbo de; Battelli, Chiara; Hetherington, Christopher J.; Ye, Min; Zhang, Hong; Maroni, Giorgia; O’Brien, Kerry L.; Magli, Maria Cristina; Borczuk, Alain C.; Varticovski, Lyuba; Kocher, Olivier; Zhang, Pu; Moon, Yaejin; Sydorenko, Nadiya; Cao, Liangxian; Davis, Thomas W.; Thakkar, Bhavin; Soo, Ross A.; Iwama, Atsushi; Lim, Bing; Halmos, Balázs; Neuberg, Donna; Tenen, Daniel G.; Levantini, Elena

doi:10.1126/scitranslmed.aad6066

Cited by 52 publications

(56 citation statements)

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“…More importantly, diminished Bmi1 levels reduced the self-renewal capacity of CSCs, which in turn correlated with lowered tumourigenic potential in vitro and in vivo. In keeping with the original observations, cells treated with a Bmi1 inhibitor became more apoptotic 77,[81][82][83] and underwent cell cycle arrest at G 0 phase. 81,82 Collectively, these studies have provided a strong rationale for including Bmi1-targeted therapy in the treatment strategies for patients presenting with malignancies displaying elevated Bmi1 expression.…”

Section: However In the Absence Of Bmi1 P16-mediated Inhibition Of supporting

confidence: 83%

Bmi1 – A Path to Targeting Cancer Stem Cells

Bakhshinyan¹,

Adile²,

Venugopal³

et al. 2017

European Oncology &Amp; Haematology

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T he Polycomb group (PcG) genes encode for proteins comprising two multiprotein complexes, Polycomb repressive complex 1 (PRC1) and Polycomb repressive complex 2 (PRC2). Although the initial discovery of PcG genes was made in Drosophila, as transcriptional repressors of homeotic (HOX) genes. Polycomb repressive complexes have been since implicated in regulating a wide range of cellular processes, including differentiation and self-renewal in normal and cancer stem cells. Bmi1, a subunit of PRC1, has been long implicated in driving self-renewal, the key property of stem cells. Subsequent studies showing upregulation of Bmi1 in several cancers correlated with increased aggressiveness, radioresistance and metastatic potential, provided rationale for development of targeted therapies against Bmi1. Although Bmi1 activity can be reduced through transcriptional, post-transcriptional and post-translational regulation, to date, the most promising approach has been through small molecule inhibitors targeting Bmi1 activity. The post-translational targeting of Bmi1 in colorectal carcinoma, lung adenocarcinoma, multiple myeloma and medulloblastoma have led to significant reduction of self-renewal capacity of cancer stem cells, leading to slower tumour progression and reduced extent of metastatic spread. Further value of Bmi1 targeting in cancer can be established through trials evaluating the combinatorial effect of Bmi1 inhibition with current 'gold standard' therapies. KeywordsPolycomb group (PcG) genes, Bmi1, Mel-18, cancer stem cells (CSCs), self-renewal Disclosure: David Bakhshinyan, Ashley A Adile, Chitra Venugopal and Sheila K Singh have nothing to disclose in relation to this article.Open Access: This article is published under the Creative Commons Attribution Noncommercial License, which permits any non-commercial use, distribution, adaptation and reproduction provided the original author(s) and source are given appropriate credit. Compliance with Ethics:This study involves a review of the literature and did not involve any studies with human or animal subjects performed by any of the authors. 1 PRC2 initiates gene silencing through the activity of histone deacetylase (HDAC), and histone methyltransferases that can methylate lysine 9 and 27 residues on histone H3 and lysine 26 on histone H1.2-6 The stable gene repression is then maintained by PRC1 through recognition of tri-methylated H3K27 (H3K27me3).3 The canonical repression pathway is initiated through trimethylation of H3K27 on the promoter of target gene by PRC2 subunit EZH1 or its paralog EZH2.2-4 The H3K27me3 mark is readily recognised by PRC1 through chromatin binding ability of its subunit CBX. The repression is further maintained through ubiquitination of lysine 119 residue on histone H2A (H2AK119ub) by RING1, a subunit of PRC1, or chromatin condensation. [7][8][9] Promoters of the polycomb target genes have been generally characterised as CpG-rich DNA sequences that are lacking other epigenetic markers.10-14 However, several other models of context depen...

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Section: However In the Absence Of Bmi1 P16-mediated Inhibition Of supporting

confidence: 83%

Bmi1 – A Path to Targeting Cancer Stem Cells

Bakhshinyan¹,

Adile²,

Venugopal³

et al. 2017

European Oncology &Amp; Haematology

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“…Bmi1 knock-down also upregulated expression of p16, p19 and p53 tumor suppressor levels in transplanted tumors. 47 Our results therefore indicate that 1,25(OH) 2 D 3 prevents tumorigenesis by inactivating oncogenes such as Bmi1 which appear to play a key role in tumorigenesis. **p < 0.01; ***p < 0.001 compared to sh-control or the WT sh-control group.…”

Section: Discussionmentioning

confidence: 66%

1,25‐Dihydroxy vitamin D prevents tumorigenesis by inhibiting oxidative stress and inducing tumor cellular senescence in mice

Chen

Yang

Qiao

et al. 2018

Intl Journal of Cancer

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Human epidemiological studies suggest that 1,25(OH) D deficiency might increase cancer incidence, but no spontaneous tumors have been reported in mice lacking 1,25(OH) D or deficient in its receptor. In our study, we detected, for the first time, diverse types of spontaneous tumors in l,25(OH) D deficient mice more than 1 year of age. This was associated with increased oxidative stress, cellular senescence and senescence-associated secretory phenotype molecules, such as hepatocyte growth factor, mediated via its receptor c-Met. Furthermore, 1,25(OH) D prevented spontaneous tumor development. We also demonstrated that l,25(OH) D deficiency accelerates allograft tumor initiation and growth by increasing oxidative stress and DNA damage, activating oncogenes, inactivating tumor suppressor genes, stimulating malignant cell proliferation and inhibiting their senescence; in contrast, supplementation with exogenous l,25(OH) D or antioxidant, or knock-down of the Bmi1 or c-Met oncogene, largely rescued the phenotypes of allograft tumors. Results from our study suggest that 1,25(OH) D deficiency enhances tumorigenesis by increasing malignant cell oxidative stress and DNA damage, stimulating microenvironmental cell senescence and a senescence-associated secretory phenotype, and activating oncogenes and inactivating tumor suppressor genes, thus increasing malignant cell proliferation. Our study provides direct evidence supporting the role of vitamin D deficiency in increasing cancer incidence. Conversely, 1,25(OH) D prevented spontaneous tumor development, suggesting that this inhibitory effect prevents the initiation and progression of tumorigenesis, thus provides a mechanistic basis for 1,25(OH) D to prevent tumorigenesis in an aging organism.

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“…Importantly, loss of C/EBPα in mouse respiratory epithelium led to respiratory failure at birth due to an arrest in the type II alveolar cell differentiation program [15]. Lung-specific C/EBPα knockout mice developed pulmonary adenocarcinoma, suggesting that the loss of C/EBPα could be an important event in the multistep process of lung tumorigenesis [19]. In this study, we found that C/EBPα expression was significantly decreased in lung adenocarcinoma tissues compared to para-carcinoma tissues.…”

Section: Discussionmentioning

confidence: 99%

“…Low expression levels of C/EBPα were found in 50% of stage II and IIIA lung adenocarcinomas, and induction of C/EBPα led to significant growth reduction attributable to proliferation arrest, morphological changes characteristic of differentiation and apoptosis [16-18]. A recent study also showed that C/EBPα was a tumor suppressor in lung cancer and that targeted B lymphoma Mo-MLV insertion region 1 homolog (BMI1) inhibition impaired tumor growth in lung adenocarcinomas with low C/EBPα expression [19]. C/EBP family members also regulate cell migration [20].…”

Section: Introductionmentioning

confidence: 99%

C/EBPα Suppresses Lung Adenocarcinoma Cell Invasion and Migration by Inhibiting β-Catenin

Lu¹,

Du²,

Yao³

et al. 2017

Cell Physiol Biochem

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Background/Aims: The transcription factor CCAAT/enhancer-binding protein α (C/EBPα) is a basic leucine zipper transcription factor that plays essential roles in tumor progression. Although decreased or absent C/EBPα expression in many cancers suggests a possible role for C/EBPα as a tumor suppressor, the functions of C/EBPα in lung adenocarcinoma remain unclear. Methods: Here, C/EBPα expression levels in 26 lung adenocarcinoma and para-carcinoma tissue samples were detected by qRT-PCR and immunohistochemistry. Cell transwell assays, wound healing assay and three-dimensional spheroid invasion assay were performed to assess the effects of C/EBPα on migration and invasion in lung adenocarcinoma cells in vitro. Western blotting was applied to analyze the potential mechanisms. Results: C/EBPα was found to be decreased in lung adenocarcinoma tissues compared to para-carcinoma tissues. Overexpression of C/EBPα significantly inhibited the migration and invasion of lung adenocarcinoma cells. In addition, C/EBPα overexpression suppressed the epithelial–mesenchymal transition (EMT) that was characterized by a gain of epithelial and loss of mesenchymal markers. Further study showed that C/EBPα suppressed the transcription of β-catenin and downregulated the levels of its downstream targets. Conclusion: Our data suggest that C/EBPα inhibits lung adenocarcinoma cell invasion and migration by suppressing β-catenin-mediated EMT in vitro. Thus, C/EBPα may be helpful as a potential target for treatment of lung adenocarcinoma.

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

Cited by 52 publications

References 50 publications

Bmi1 – A Path to Targeting Cancer Stem Cells

Bmi1 – A Path to Targeting Cancer Stem Cells

1,25‐Dihydroxy vitamin D prevents tumorigenesis by inhibiting oxidative stress and inducing tumor cellular senescence in mice

C/EBPα Suppresses Lung Adenocarcinoma Cell Invasion and Migration by Inhibiting β-Catenin

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