RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells

Girard, Nathalie; Tremblay, Mathieu; Humbert, Magali; Grondin, Benoı̂t; Haman, André; Labrecque, Jean; Chen, Bing; Chen, Zhu; Chen, Sai‐Juan; Hoang, Trang

doi:10.1073/pnas.1310067110

Cited by 28 publications

(19 citation statements)

References 39 publications

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“…Furthermore, HDACs are critical for the optimal oncogenic activity of leukemia fusion proteins. For example, AML1-ETO, PML-RARα and RARα-PLZF cause transcriptional repression of genes responsible for hematopoietic differentiation via recruitment of HDAC1/3, thus contributing substantially to leukemogenesis [99][100][101][102][103][104][105][106][107]. Given that the expression and activity of HDACs are closely related to the etiology of hematological malignancies, HDACs are hot targets for clinical drug development.…”

Section: The Clinical Implications Of Hdacis In Malignant Hematopoiesismentioning

confidence: 99%

Role of HDACs in normal and malignant hematopoiesis

2020

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Normal hematopoiesis requires the accurate orchestration of lineage-specific patterns of gene expression at each stage of development, and epigenetic regulators play a vital role. Disordered epigenetic regulation has emerged as a key mechanism contributing to hematological malignancies. Histone deacetylases (HDACs) are a series of key transcriptional cofactors that regulate gene expression by deacetylation of lysine residues on histone and nonhistone proteins. In normal hematopoiesis, HDACs are widely involved in the development of various lineages. Their functions involve stemness maintenance, lineage commitment determination, cell differentiation and proliferation, etc. Deregulation of HDACs by abnormal expression or activity and oncogenic HDAC-containing transcriptional complexes are involved in hematological malignancies. Currently, HDAC family members are attractive targets for drug design, and a variety of HDAC-based combination strategies have been developed for the treatment of hematological malignancies. Drug resistance and limited therapeutic efficacy are key issues that hinder the clinical applications of HDAC inhibitors (HDACis). In this review, we summarize the current knowledge of how HDACs and HDAC-containing complexes function in normal hematopoiesis and highlight the etiology of HDACs in hematological malignancies. Moreover, the implication and drug resistance of HDACis are also discussed. This review presents an overview of the physiology and pathology of HDACs in the blood system.

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Section: The Clinical Implications Of Hdacis In Malignant Hematopoiesismentioning

confidence: 99%

Role of HDACs in normal and malignant hematopoiesis

2020

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“…31 Besides, the function of CEBPα in cell proliferation arrest and tumor suppression had been extensively studied. [32][33][34] Here we found that more CEBPα mRNAs (Supplementary Figure 3D) and proteins ( Figure 3a) were found in lincRNA-uc002yug.2-low cells. And, a significant negative correlation (R 2 = 0.162, P = 0.046) between the transcriptional levels of RUNX1a and CEBPα was found, whereas a significant negative correlation (R 2 = 0.246, P = 0.013) existed between the transcriptional levels of lincRNA-uc002yug.2 and CEBPα (Figure 3b).…”

Section: Runx1 Affects Cebpα Gene Expression Via Conserved Promoter Amentioning

confidence: 56%

LincRNA-uc002yug.2 involves in alternative splicing of RUNX1 and serves as a predictor for esophageal cancer and prognosis

Jian

Deng

et al. 2014

Oncogene

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Long intergenic noncoding RNAs (lincRNAs) have critical regulatory roles in cancer biology; however, the contributions of lincRNAs to esophageal squamous cell carcinoma (ESCC) have been infrequently explored. The aim of this study was to explore the contribution of lincRNAs, located at ESCC susceptibility loci identified by genome-wide association studies, to the risk and prognosis of ESCC. The associations between lincRNAs and the risk and prognosis of ESCC were analyzed in 358 diagnosed patients from eastern China, and the findings were validated in 326 additional patients from southern China. Functional relevance of lincRNAs was further examined by biochemical assays. We found that lincRNA-uc002yug.2 was commonly overexpressed in ESCC compared with paired peritumoral tissue in eastern and southern Chinese populations. The expression levels of lincRNA-uc002yug.2 in ESCC might be a prognostic factor for survival. Moreover, lincRNA-uc002yug.2 promoted a combination of RUNX1 and alternative splicing (AS) factors in the nucleus to produce more RUNX1a, the short isoform and inhibitor of RUNX1, and reduce CEBPα (CCAAT/enhancer-binding protein-α) gene expression, thereby promoting ESCC progression. These results indicated that lincRNA-uc002yug.2 might involve in AS of RUNX1/AML1 and serve as a predictor for esophageal cancer and prognosis.

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“…Molecular studies reveal that the PLZF/RARA fusion protein acts mainly as an epigenetic regulator of its target genes by directly interacting with the Polycomb protein Bmi‐1 to recruit PRC1 to the retinoic acid response elements . On the other hand, RARA/PLZF recruits HDAC1 to cause histone H3 deacetylation at the C/EBPα locus, leading to a decrease in the expression of C/EBPα target genes, and thus inhibiting myeloid differentiation to promote self‐renewal of myeloid progenitors .…”

Section: Stem Cell Self‐renewalmentioning

confidence: 99%

Concise Review: Balancing Stem Cell Self-Renewal and Differentiation with PLZF

et al. 2016

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In recent years, the highly conserved promyelocytic leukemia zinc finger (PLZF, also known as ZBTB16, ZNF145) has attracted attention as a multifunctional transcription factor involved in major biological processes during development. As a transcription factor, PLZF shows tight regulation in its cell-type-specific and stage-specific expression patterns. Emerging evidence shows that PLZF regulates the balance of self-renewal and differentiation in stem cells. However, the gene regulatory network of PLZF is only beginning to be understood. In this review, we discuss the diverse functions of PLZF, in particular its role in self-renewal versus differentiation of stem cells. We also discuss the current state of knowledge on the gene regulatory network of PLZF, in conjunction with its upstream factors, post-translational modifications and binding cofactors for multiprotein complexes. This review aims to provide the reader with an in-depth understanding of the molecular mechanisms underlying PLZF and the potential applications in tissue regeneration. STEM CELLS 2016;34:277-287 SIGNIFICANCE STATEMENTSIGNIFICANCE STATEMENT Stem cells posses the unique ability to maintain multipotency and selfrenew. Stem cell fate decisions, to self-renew or differentiate, is a key step in the therapeutic use of stem cells for regenerative medicine. In recent years, the highly conserved promyelocytic leukemia zinc finger (PLZF, also known as ZBTB16, ZNF145) has attracted attention as a multifunctional transcription factor involved in stem cell biology. PLZF is expressed in long-term HSCs (LT-HSCs), spermatogonial stem cells and neural progenitors to maintain their selfrenewal. Interestingly, PLZF is also expressed during myeloid differentiation, na€ ıve T cells differentiating into effector T cells, and osteochondral differentiation of MSCs into bone and cartilage. Our labs have substantial experience with the effects of PLZF on the osteochondral differentiation of MSCs, and we would like to propose a model for how PLZF might balance stem cell self-renewal and differentiation as a transcription factor.

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RARα-PLZF oncogene inhibits C/EBPα function in myeloid cells

Cited by 28 publications

References 39 publications

Role of HDACs in normal and malignant hematopoiesis

Role of HDACs in normal and malignant hematopoiesis

LincRNA-uc002yug.2 involves in alternative splicing of RUNX1 and serves as a predictor for esophageal cancer and prognosis

Concise Review: Balancing Stem Cell Self-Renewal and Differentiation with PLZF

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