Runx3 at the interface of immunity, inflammation and cancer

Lotem, Joseph; Levanon, Ditsa; Negreanu, Varda; Bauer, Omri; Hantisteanu, Shay; Dicken, Joseph; Groner, Yoram

doi:10.1016/j.bbcan.2015.01.004

Cited by 52 publications

(52 citation statements)

References 147 publications

(240 reference statements)

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“…RUNX1 belongs to the RUNX family of transcription factors (RUNX1–3) that share the ability to bind to the RUNX motif via dimerization with CBFβ (de Bruijn and Speck, 2004; Ito, 2004). The current literature supports the notion that RUNXs have distinct biological/pathological functions, owning to their tissue/cell-specific expression patterns (Okuda et al, 1996; Zhang et al, 2000; Li et al, 2002; Lotem et al, 2015). …”

Section: Transcriptional Mechanisms Of Aml1-etosupporting

confidence: 80%

New insights into transcriptional and leukemogenic mechanisms of AML1-ETO and E2A fusion proteins

Guo

Steinauer

et al. 2016

Front. Biol.

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BACKGROUND Nearly 15% of acute myeloid leukemia (AML) cases are caused by aberrant expression of AML1-ETO, a fusion protein generated by the t(8;21) chromosomal translocation. Since its discovery, AML1-ETO has served as a prototype to understand how leukemia fusion proteins deregulate transcription to promote leukemogenesis. Another leukemia fusion protein, E2A-Pbx1, generated by the t(1;19) translocation, is involved in acute lymphoblastic leukemias (ALLs). While AML1-ETO and E2A-Pbx1 are structurally unrelated fusion proteins, we have recently shown that a common axis, the ETO/E-protein interaction, is involved in the regulation of both fusion proteins, underscoring the importance of studying protein–protein interactions in elucidating the mechanisms of leukemia fusion proteins. OBJECTIVE In this review, we aim to summarize these new developments while also providing a historic overview of the related early studies. METHODS A total of 218 publications were reviewed in this article, a majority of which were published after 2004.We also downloaded 3D structures of AML1-ETO domains from Protein Data Bank and provided a systematic summary of their structures. RESULTS By reviewing the literature, we summarized early and recent findings on AML1-ETO, including its protein–protein interactions, transcriptional and leukemogenic mechanisms, as well as the recently reported involvement of ETO family corepressors in regulating the function of E2A-Pbx1. CONCLUSION While the recent development in genomic and structural studies has clearly demonstrated that the fusion proteins function by directly regulating transcription, a further understanding of the underlying mechanisms, including crosstalk with other transcription factors and cofactors, and the protein–protein interactions in the context of native proteins, may be necessary for the development of highly targeted drugs for leukemia therapy.

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Section: Transcriptional Mechanisms Of Aml1-etosupporting

confidence: 80%

New insights into transcriptional and leukemogenic mechanisms of AML1-ETO and E2A fusion proteins

Guo

Steinauer

et al. 2016

Front. Biol.

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“…RUNX3 is a member of the runt-related gene family. RUNX3 plays important roles in growth, development, immune regulation and tumourigenesis [17,18]. We identified RUNX3 as a direct target of miR-210 using a microRNA target prediction tool (miRanda, http:// www.microrna.org/microrna/getMrna.do?gene=864&utr=2888&orga nism=9606#).…”

Section: Introductionmentioning

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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“…However, this has been contradicted by other reports of RUNX3 behaving more like an oncogene, with overexpression leading to tumorigenesis. [21][22][23] A recent review by Lotem [24] disputes the idea that RUNX3 is a cell-autonomous tumor suppressor, arguing instead that the accumulated literature suggests a complex interplay of immune mechanisms may underlie the pathogenesis of RUNX3 in cancer.…”

Section: Discussionmentioning

confidence: 96%

Loss of RUNX3 expression is an independent adverse prognostic factor in diffuse large B-cell lymphoma

Duncan

Zheng

Varambally

et al. 2016

Leukemia & Lymphoma

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Runt-related transcription factor-3 (RUNX3) is an apoptotic factor correlated with tumorigenesis and cancer progression. Enhancer of zeste homolog-2 (EZH2), a histone methyltransferase, has been shown to mediate silencing of RUNX3. We investigated RUNX3 and EZH2 expression in diffuse large B-cell lymphoma (DLBCL). A chart review was conducted and tissue-microarray (TMA) was constructed using archived tissue from 83 DLBCL cases. RUNX3 and EZH2 protein expression was correlated with immunophenotypic subtypes and survival. Loss of RUNX3 was observed in 20 cases; EZH2 expression was observed in 59 cases. RUNX3-negative tumors had significantly lower overall and recurrence-free survival (log-rank test, p < 0.0001 for each). No correlation was found between RUNX3 and EZH2 staining (r = 0.14; p = 0.2). Results suggest a role for the RUNX3 gene in the pathogenesis of DLBCL. Loss of RUNX3 expression strongly correlated with adverse prognosis, independent of subtype. Further studies are warranted to elucidate the biology and prognostic utility of RUNX3 in DLBCL.

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Runx3 at the interface of immunity, inflammation and cancer

Cited by 52 publications

References 147 publications

New insights into transcriptional and leukemogenic mechanisms of AML1-ETO and E2A fusion proteins

New insights into transcriptional and leukemogenic mechanisms of AML1-ETO and E2A fusion proteins

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

Loss of RUNX3 expression is an independent adverse prognostic factor in diffuse large B-cell lymphoma

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