The transcription factor CBFB suppresses breast cancer through orchestrating translation and transcription

Malik, Navdeep; Yan, Hualong; Moshkovich, Nellie; Palangat, Murali; Yang, Howard H.; Sanchez, Vanesa C.; Cai, Zhuo; Peat, Tyler J.; Jiang, Shunlin; Liu, Chengyu; Lee, Maxwell; Mock, Beverly A.; Yuspa, Stuart H.; Larson, Daniel R.; Wakefield, Lalage M.; Huang, Jing

doi:10.1038/s41467-019-10102-6

Cited by 65 publications

(73 citation statements)

References 34 publications

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“…Our study establishes that inhibition of RUNX1 DNA binding through pharmacological disruption of the RUNX1-CBFβ interaction specifically elicits an epithelial-to-mesenchymal transition that accompanies changes in critical genes and pathways involved in EMT. Recent findings have identified a non-canonical, posttranscriptional role for CBFβ in mammary epithelial cells [26]. Our results indicate that, in addition to posttranscriptional regulation of gene expression, CBFβ plays important roles in transcriptional activity of DNA binding members of the RUNX family.…”

Section: Discussionsupporting

confidence: 51%

“…Conversely, several studies have shown that lineage restricted depletion of CBFβ only partially recapitulates phenotypes observed with deletion of the DNA binding RUNX factors [19,[22][23][24][25], suggesting that not all transcriptional regulatory activity of these proteins requires CBFβ. Furthermore, a recent study has shown that CBFβ functions post-transcriptionally to regulate gene expression in breast epithelial cells [26]. Together, these observations highlight knowledge gaps in the mechanistic understanding of gene regulation by the RUNX-CBFβ transcriptional complex.…”

Section: Introductionmentioning

confidence: 84%

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Inhibition of the RUNX1-CBFβ transcription factor complex compromises mammary epithelial cell identity: a phenotype potentially stabilized by mitotic gene bookmarking

et al. 2020

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RUNX1 has recently been shown to play an important role in determination of mammary epithelial cell identity. However, mechanisms by which loss of the RUNX1 transcription factor in mammary epithelial cells leads to epithelial-to-mesenchymal transition (EMT) are not known. Here, we report that interaction between RUNX1 and its heterodimeric partner CBFβ is essential for sustaining mammary epithelial cell identity. Disruption of RUNX1-CBFβ interaction, DNA binding, and association with mitotic chromosomes alters cell morphology, global protein synthesis, and phenotyperelated gene expression. During interphase, RUNX1 is organized as punctate, predominantly nuclear, foci that are dynamically redistributed during mitosis, with a subset localized to mitotic chromosomes. Genome-wide RUNX1 occupancy profiles for asynchronous, mitotically enriched, and early G1 breast epithelial cells reveal RUNX1 associates with RNA Pol II-transcribed protein coding and long non-coding RNA genes and RNA Pol I-transcribed ribosomal genes critical for mammary epithelial proliferation, growth, and phenotype maintenance. A subset of these genes remains occupied by the protein during the mitosis to G1 transition. Together, these findings establish that the RUNX1-CBFβ complex is required for maintenance of the normal mammary epithelial phenotype and its disruption leads to EMT. Importantly, our results suggest, for the first time, that RUNX1 mitotic bookmarking of a subset of epithelial-related genes may be an important epigenetic mechanism that contributes to stabilization of the mammary epithelial cell identity.

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Section: Discussionsupporting

confidence: 51%

Section: Introductionmentioning

confidence: 84%

Inhibition of the RUNX1-CBFβ transcription factor complex compromises mammary epithelial cell identity: a phenotype potentially stabilized by mitotic gene bookmarking

et al. 2020

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“…Pathway analysis of breast cancer genes shows enrichment of pathways involved in gene expression regulation governed by TP53, RUNX1 and PTEN which includes pathways that regulates estrogen-mediated transcription. CBFB deletion leads to expression loss of RUNX1[21], which can no longer regulate NOTCH signalling by repression, which is confirmed by pathway analysis. Some apoptosis pathways are enriched that include CDH1 and TP53 genes.…”

Section: Resultsmentioning

confidence: 92%

“…Genes identified for breast cancer was validated by supporting literature. CBFB [21] and PTEN [22, 23] is a known TSG in breast cancer. PTEN is found to be under-expressed in breast cancer [24, 25].…”

Section: Resultsmentioning

confidence: 99%

Novel ratio-metric features enable the identification of new driver genes across cancer types

Sudhakar

Rengaswamy

Raman

2020

Preprint

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An emergent area of cancer genomics has been the identification of driver genes. Driver genes confer a selective growth advantage to the cell and push it towards tumorigenesis. Functionally, driver genes can be divided into two categories, tumour suppressor genes (TSGs) and oncogenes (OGs), which have distinct mutation type profiles. While several driver genes have been discovered, many remain undiscovered, especially those that are mutated at a low frequency across samples. The current methods are not sufficient to predict all driver genes because the underlying characteristics of these genes are not yet well understood. Thus, to predict novel genes, we need to define new features and models that are not biased and identify genes that might otherwise be overshadowed by mutation profiles of recurrent driver genes. In this study, we define new features and build a model to identify novel driver genes. We overcome overfitting and show that certain mutation types such as nonsense mutations are more important for classification. Some known cancer driver genes, which are predicted by the model as TSGs with high probability are ARID1A, TP53, and RB1. In addition to these known genes, potential driver genes predicted are CD36, ZNF750 and ARHGAP35 as TSGs and TAB3 as an oncogene. Overall, our approach surmounts the issue of low recall and bias towards genes with high mutation rates and predicts potential novel driver genes for further experimental screening.

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“…It encodes a transcription factor, which makes a complex by attaching to RUNX1 2 . This complex can transcriptionally repress the oncogenic NOTCH signaling pathway (Malik et al, 2019). TBX3 is a substantial gene in Primary subtype, which is needed for normal breast development 3 .…”

Section: Finding the Gene Signature For Each Subtypementioning

confidence: 99%

Classifying Breast Cancer Molecular Subtypes by Using Deep Clustering Approach

Rohani

Eslahchi

2020

Front. Genet.

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Cancer is a complex disease with a high rate of mortality. The characteristics of tumor masses are very heterogeneous; thus, the appropriate classification of tumors is a critical point in the effective treatment. A high level of heterogeneity has also been observed in breast cancer. Therefore, detecting the molecular subtypes of this disease is an essential issue for medicine that could be facilitated using bioinformatics. This study aims to discover the molecular subtypes of breast cancer using somatic mutation profiles of tumors. Nonetheless, the somatic mutation profiles are very sparse. Therefore, a network propagation method is used in the gene interaction network to make the mutation profiles dense. Afterward, the deep embedded clustering (DEC) method is used to classify the breast tumors into four subtypes. In the next step, gene signature of each subtype is obtained using Fisher's exact test. Besides the enrichment of gene signatures in numerous biological databases, clinical and molecular analyses verify that the proposed method using mutation profiles can efficiently detect the molecular subtypes of breast cancer. Finally, a supervised classifier is trained based on the discovered subtypes to predict the molecular subtype of a new patient. The code and material of the method are available at: https://github.com/nrohani/MolecularSubtypes.

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The transcription factor CBFB suppresses breast cancer through orchestrating translation and transcription

Cited by 65 publications

References 34 publications

Inhibition of the RUNX1-CBFβ transcription factor complex compromises mammary epithelial cell identity: a phenotype potentially stabilized by mitotic gene bookmarking

Inhibition of the RUNX1-CBFβ transcription factor complex compromises mammary epithelial cell identity: a phenotype potentially stabilized by mitotic gene bookmarking

Novel ratio-metric features enable the identification of new driver genes across cancer types

Classifying Breast Cancer Molecular Subtypes by Using Deep Clustering Approach

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