Eya2, a Target Activated by Plzf, Is Critical for <i>PLZF-RARA</i>-Induced Leukemogenesis

Ono, Ryoichi; Masuya, Masahiro; Ishii, S; Katayama, Naoyuki; Nosaka, Tetsuya

doi:10.1128/mcb.00585-16

Cited by 18 publications

(29 citation statements)

References 59 publications

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“…Transcription factors were also overexpressed in the HPV+ Blue network, such as YBX2, DMRTA2 and EYA2. Most of these TF have been described as overexpressed in different types of cancers, including ovarian, testis and breast cancer in the case of YBX2 (37, 38), and breast cancer, lung cancer and acute myeloid leukemia in the case of EYA2 (39,40). DMRTA2, on the other hand, is also expressed in the spermatogenesis of the testis, and regulates the cyclin-dependent kinase CDKN2c (41), in addition to maintaining neuroprogenitor cells in the cell cycle (42).…”

Section: Discussionmentioning

confidence: 99%

Distinct co-expression networks using multi-omic data reveal novel interventional targets in HPV-positive and negative head-and-neck squamous cell cancer

Costa

Boroni

Soares

2017

Preprint

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The human papillomavirus (HPV) is present in a significant fraction of head-and-neck squamous cell cancer (HNSCC). However, a comprehensive understanding of disease progression profiles comparing HPV+ and HPV-HNSCC cases is still lacking. The main goal of this study was to identify distinct co-expression patterns between HPV+ and HPV-HNSCC and to provide insights into potential regulatory mechanisms/effects (such as methylation and mutation) within the analyzed networks. For conducting this, we selected 276 samples from The Cancer Genome Atlas database comprising data of gene expression, methylation profiles and mutational patterns, in addition to clinical information (HPV status and tumor staging). We further added external information such as the identification of transcription factors to the networks. Genes were selected as differentially expressed and differentially methylated based on HPV status, of which 12 genes were doubly selected, including SYCP2, GJB6, FLRT3, PITX2 and CCNA1. Weight correlation network analysis was used to identify co-expression modules and a systematic approach was applied to refine them and identify key regulatory elements integrating results from the other omics. Three main modules were associated with distinct co-expression patterns in HPV+ versus HPV-HNSCC. The molecular signatures found were mainly related to cell fate specification, keratinocyte differentiation, focal adhesion and regulation of protein oligomerization. This study provides comprehensive insights into complex genetic and epigenetic particularities in the development and progression of HNSCC in patients according to HPV status, identifying unseen gene interactions, and may contribute to unveiling specific genes/pathways as novel therapeutic targets for HNSCC.

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Section: Discussionmentioning

confidence: 99%

Distinct co-expression networks using multi-omic data reveal novel interventional targets in HPV-positive and negative head-and-neck squamous cell cancer

Costa

Boroni

Soares

2017

Preprint

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“…The target sequences against the Eya2 and luciferase genes were 5'-GTGTTTCAG AGACAATCAT-3' (shE09) and 5'-GCCTTATGCCGCCAT CTTG-3' (shE12), and 5'-GGCTATGAAGAGATACGCC-3' (shLuc). The shE09 and shE12 were two out of twelve sequences (shE01-shE12) designed for Eya2 knockdown, which exerted the most efficient effects (35). To design a short hairpin structure, a loop sequence (5'-CTTCAAGAGAG-3') was used (35).…”

Section: Construction Of the Plasmids And Retroviral Vectorsmentioning

confidence: 99%

“…The shE09 and shE12 were two out of twelve sequences (shE01-shE12) designed for Eya2 knockdown, which exerted the most efficient effects (35). To design a short hairpin structure, a loop sequence (5'-CTTCAAGAGAG-3') was used (35). Short hairpin RNA (shRNA) sequence(s) against Eya2 or luciferase were cloned into the retroviral vector pMXsU6-KO (36).…”

Section: Construction Of the Plasmids And Retroviral Vectorsmentioning

confidence: 99%

“…Following quantification of the expression of samples using the quantification cycle (2 -ΔΔCT ) method (43) and performing normalization relative to β-2-microglobulin (B2m), the relative expression was calculated. The sequences of the primers used (Eya1, Eya2, Eya3, Eya4, and B2m) have been previously described (35,36). For the ChIP-qPCR analysis, PCR was performed for 40 cycles (98˚C for 10 sec, 60˚C for 10 sec and 68˚C for 34 sec) in a total volume of 20 µl.…”

Section: Reverse Transcription (Rt) Qpcr Rt-qpcr and Rt-pcrmentioning

confidence: 99%

“…By contrast, silencing of EYA2 promotes tumor growth in pancreatic adenocarcinoma, indicating the tumor suppressive function of EYA2 (33). Eya2 is differentially expressed in mouse long-term hematopoietic stem cells (34) and confers an aberrant self-renewal capacity in HSPCs (35). In addition, Eya2 is critically involved in leukemogenesis via zinc finger and BTB domain containing 16-retinoic acid receptor-α (PLZF-RARA) resulting from t(11;17)(q23;q21) in patients with acute promyelocytic leukemia (35).…”

Section: Introductionmentioning

confidence: 99%

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Eya2 is critical for the E2A‑HLF‑mediated immortalization of mouse hematopoietic stem/progenitor cells

2019

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The immunoglobulin enhancer-binding factor/ hepatic leukemia factor (E2A-HLF) oncogenic fusion gene, generated by t(17;19)(q22;p13) translocation in childhood B-cell acute lymphoblastic leukemia with a very poor prognosis, encodes a chimeric transcription factor in which the transactivation domains of E2A are fused to the DNA-binding and dimerization domain of HLF.E2A-HLF has been demonstrated to have an anti-apoptotic effect. However, the molecular mechanism underlying E2A-HLF-mediated leukemogenesis remains unclear. The present study identified EYA transcriptional coactivator and phosphatase 2 (Eya2), the forced expression of which is known to immortalize mouse hematopoietic stem/progenitor cells (HSPCs), as a direct target molecule downstream of E2A-HLF. E2A-HLF-immortalized mouse HSPCs expressed Eya2 at a high level in the aberrant self-renewal program. Chromatin immunoprecipitation-quantitative polymerase chain reaction and a reporter assay revealed that E2A-HLF enhanced the Eya2 expression by binding to the promoter region containing the E2A-HLF-binding consensus sequence. Eya2 knockdown in E2A-HLF-immortalized cells resulted in reduced colony-forming efficiency. These results suggest a critical role of Eya2 in E2A-HLF-mediated leukemogenesis.

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The important roles of protein SUMOylation in the occurrence and development of leukemia and clinical implications

Zhao

Zhang

Chen

et al. 2020

Journal Cellular Physiology

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Leukemia is a severe malignancy of the hematopoietic system, which is characterized by uncontrolled proliferation and dedifferentiation of immature hematopoietic precursor cells in the lymphatic system and bone marrow. Leukemia is caused by alterations of the genetic and epigenetic regulation of processes underlying hematologic malignancies, including SUMO modification (SUMOylation). Small ubiquitin‐like modifier (SUMO) proteins covalently or noncovalently conjugate and modify a large number of target proteins via lysine residues. SUMOylation is a small ubiquitin‐like modification that is catalyzed by the SUMO‐specific activating enzyme E1, the binding enzyme E2, and the ligating enzyme E3. SUMO is covalently linked to substrate proteins to regulate the cellular localization of target proteins and the interaction of target proteins with other biological macromolecules. SUMOylation has emerged as a critical regulatory mechanism for subcellular localization, protein stability, protein–protein interactions, and biological function and thus regulates normal life activities. If the SUMOylation process of proteins is affected, it will cause a cellular reaction and ultimately lead to various diseases, including leukemia. There is growing evidence showing that a large number of proteins are SUMOylated and that SUMOylated proteins play an important role in the occurrence and development of various types of leukemia. Targeting the SUMOylation of proteins alone or in combination with current treatments might provide powerful targeted therapeutic strategies for the clinical treatment of leukemia.

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Eya2, a Target Activated by Plzf, Is Critical for PLZF-RARA-Induced Leukemogenesis

Cited by 18 publications

References 59 publications

Distinct co-expression networks using multi-omic data reveal novel interventional targets in HPV-positive and negative head-and-neck squamous cell cancer

Distinct co-expression networks using multi-omic data reveal novel interventional targets in HPV-positive and negative head-and-neck squamous cell cancer

Eya2 is critical for the E2A‑HLF‑mediated immortalization of mouse hematopoietic stem/progenitor cells

The important roles of protein SUMOylation in the occurrence and development of leukemia and clinical implications

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