The RUNX family: developmental regulators in cancer

Ito, Yoshiaki; Bae, Suk‐Chul; Chuang, Linda Shyue Huey

doi:10.1038/nrc3877

Cited by 328 publications

(365 citation statements)

References 190 publications

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“…Moreover, Runx3-deficient mice showed accelerated gastric tumor development when challenged with mutagen. 1 Taken together with our findings on RUNX in mitosis, we hypothesize that RUNX proteins ensure cellular identity through 2 main mechanisms: (1) maintain cell phenotype through its transcriptional programs; (2) safeguard genome integrity through its non-transcriptional regulation of mitosis and DNA repair. Conceptually, the transcriptional and non-transcriptional roles of RUNX proteins are mutually exclusive functions that represent 2 sides of the same coin.…”

supporting

confidence: 71%

“…The RUNX family is profoundly implicated in cancer: dysregulation of RUNX genes has been linked to initiation as well progression of diverse cancer types. 1 RUNX proteins derived their name from the Runt domain, an evolutionarily conserved 128-amino acid region, which endows RUNX proteins with sequence-specific DNA binding. Interestingly, unlike many transcription factors in mitosis, RUNX proteins are found on key mitotic structures such as the centrosome, spindle and midbody 2 -raising the intriguing possibility that RUNX proteins play active roles in mitosis, a cell cycle phase traditionally associated with major cessation of transcription.…”

mentioning

confidence: 99%

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Aurora kinase and RUNX: Reaching beyond transcription

2016

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supporting

confidence: 71%

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confidence: 99%

Aurora kinase and RUNX: Reaching beyond transcription

2016

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“…RUNX3 is a tumour suppressor gene that functions in the early stage, and it is involved in immunity, inflammation, apoptosis and development 17, 38. As shown in the study by Lee et al .…”

Section: Discussionmentioning

confidence: 99%

A positive feedback loop promotes HIF‐1α stability through miR‐210‐mediated suppression of RUNX3 in paraquat‐induced EMT

Zhu

Meng

Xie

et al. 2017

J Cellular Molecular Medi

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Irreversible pulmonary fibrosis induced by paraquat (PQ) poisoning is the major cause of death in patients with PQ poisoning. The epithelial–mesenchymal transition (EMT) is postulated to be one of the main mechanisms of pulmonary fibrosis. Here, we investigated the role of miR‐210 in PQ‐induced EMT and its relationship with hypoxia‐inducible factor‐1α (HIF‐1α). Western blotting, immunofluorescence, immunoprecipitation and other methods were used in this study. We found that miR‐210 expression was significantly increased after PQ poisoning, and it may be regulated by HIF‐1α. Overexpression of miR‐210 further increased the HIF‐1α protein level and promoted EMT. Moreover, miR‐210 knock‐down reduced the HIF‐1α protein level and decreased the degree of EMT. Runt‐related transcription factor‐3 (RUNX3), a direct target of miR‐210, was inhibited by miR‐210 in response to PQ poisoning. RUNX3 increased the hydroxylation ability of prolyl hydroxylase domain‐containing protein 2 (PHD2), a key enzyme that promotes HIF‐1α degradation. PHD2 immunoprecipitated with RUNX3 and its level changed similarly to that of RUNX3. The expression of the HIF‐1α protein was significantly reduced when RUNX3 was overexpressed. HIF‐1α protein levels were markedly increased when RUNX3 was silenced. Based on these results, a positive feedback loop may exist between miR‐210 and HIF‐1α. The mechanism may function through miR‐210‐mediated repression of RUNX3, which further decreases the hydroxylation activity of PHD2, enhances the stability of HIF‐1α, and promotes PQ‐induced EMT, aggravating the progression of pulmonary fibrosis. This study further elucidates the mechanism of PQ‐induced pulmonary fibrosis and may provide a new perspective for the future development of therapies.

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“…Runt-related transcription factors (RUNX) are master regulators of cell-fate decisions (3). Mutation or dysregulation of RUNX genes have been associated with diverse cancer types (3).…”

mentioning

confidence: 99%

“…Mutation or dysregulation of RUNX genes have been associated with diverse cancer types (3). Unlike many transcription factors (e.g., Ets-1 and Oct-1) (4), RUNX proteins are retained at the condensed mitotic chromatin, where they maintain epigenetic memory and ensure proper transmission of gene expression patterns to progeny cells; RUNX2 binds to the promoters of various cell cycle-and cell fate-related genes and regulates histone modifications during mitosis (5); RUNX2 and RUNX3 bind to regulatory regions of rRNA genes and are associated with their repression (6,7).…”

mentioning

confidence: 99%

Aurora kinase-induced phosphorylation excludes transcription factor RUNX from the chromatin to facilitate proper mitotic progression

Chuang

Khor

Lai

et al. 2016

Proc. Natl. Acad. Sci. U.S.A.

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The Runt-related transcription factors (RUNX) are master regulators of development and major players in tumorigenesis. Interestingly, unlike most transcription factors, RUNX proteins are detected on the mitotic chromatin and apparatus, suggesting that they are functionally active in mitosis. Here, we identify key sites of RUNX phosphorylation in mitosis. We show that the phosphorylation of threonine 173 (T173) residue within the Runt domain of RUNX3 disrupts RUNX DNA binding activity during mitotic entry to facilitate the recruitment of RUNX proteins to mitotic structures. Moreover, knockdown of RUNX3 delays mitotic entry. RUNX3 phosphorylation is therefore a regulatory mechanism for mitotic entry. Cancer-associated mutations of RUNX3 T173 and its equivalent in RUNX1 further corroborate the role of RUNX phosphorylation in regulating proper mitotic progression and genomic integrity.C ell division is a highly ordered process comprising multiple steps that lead to dramatic changes to the cell architecture. Events such as cell rounding, chromatin condensation, spindle assembly, nuclear envelope disassembly, and cytokinesis involve numerous proteins, whose activities are tightly coordinated by mitotic kinases and proteasome-mediated degradation (1). Given that most transcription has stopped (2), the roles of transcription factors during mitosis are ill explored.Runt-related transcription factors (RUNX) are master regulators of cell-fate decisions (3). Mutation or dysregulation of RUNX genes have been associated with diverse cancer types (3). Unlike many transcription factors (e.g., Ets-1 and Oct-1) (4), RUNX proteins are retained at the condensed mitotic chromatin, where they maintain epigenetic memory and ensure proper transmission of gene expression patterns to progeny cells; RUNX2 binds to the promoters of various cell cycle-and cell fate-related genes and regulates histone modifications during mitosis (5); RUNX2 and RUNX3 bind to regulatory regions of rRNA genes and are associated with their repression (6, 7). RUNX1 positively regulates the transcription of various spindle assembly checkpoint genes, such as BUB1 and NEK6 (8). These findings suggest that RUNX proteins are important for the accurate transmission of genetic information during mitosis and that defects in RUNX genes might contribute to aneuploidy and loss of cell identity.Aside from binding to the chromatin, RUNX proteins also associate with microtubules (9, 10). RUNX3 molecules are detected at key mitotic structures such as the centrosome, mitotic spindle, and midbody (11). Likewise, RUNX-binding partner CBFβ was found at the midbody and implicated in cytokinesis (12). The reason why RUNX proteins are present at non-DNA sites (i.e., mitotic apparatus) during mitosis is unknown. An intriguing observation is the hyperphosphorylation of RUNX proteins during mitosis (13,14). RUNX2 is phosphorylated by mitotic kinase CDK1-cyclin B1 (14, 15) and dephosphorylated at mitotic exit by the PP1/PP2A phosphatase (14). CDK1-mediated phosphorylation of RUNX2 enhanc...

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The RUNX family: developmental regulators in cancer

Cited by 328 publications

References 190 publications

Aurora kinase and RUNX: Reaching beyond transcription

Aurora kinase and RUNX: Reaching beyond transcription

A positive feedback loop promotes HIF‐1α stability through miR‐210‐mediated suppression of RUNX3 in paraquat‐induced EMT

Aurora kinase-induced phosphorylation excludes transcription factor RUNX from the chromatin to facilitate proper mitotic progression

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