Histone lysine demethylase KDM5B maintains chronic myeloid leukemia via multiple epigenetic actions
| Autor: | Xuanbing Wang, Zhikai He, Lin Li, Yan Zheng, Yuk Man Lam, Lanlan Zheng, Ray Kit Ng, Zhongshan Cheng, Yonghong Zhang, Shen Xue, Magdaleena Naemi Mbadhi, Ying Liu, Li Chong Chan, Chen Li, Jingxuan Zhang |
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| Rok vydání: | 2019 |
| Předmět: |
0301 basic medicine
Cancer Research Jumonji Domain-Containing Histone Demethylases Biology Epigenesis Genetic 03 medical and health sciences 0302 clinical medicine Histone demethylation hemic and lymphatic diseases Leukemia Myelogenous Chronic BCR-ABL Positive Histone methylation Genetics Transcriptional regulation Humans Epigenetics Molecular Biology Regulation of gene expression Gene Expression Regulation Leukemic Gene Expression Profiling Myeloid leukemia Nuclear Proteins Cell Differentiation Cell Biology Hematology Hematopoietic Stem Cells Cell biology Neoplasm Proteins Repressor Proteins 030104 developmental biology 030220 oncology & carcinogenesis biology.protein H3K4me3 Demethylase K562 Cells |
| Zdroj: | Experimental hematology. 82 |
| ISSN: | 1873-2399 |
| Popis: | The histone lysine demethylase KDM5 family is implicated in normal development and stem cell maintenance by epigenetic modulation of histone methylation status. Deregulation of the KDM5 family has been reported in various types of cancers, including hematological malignancies. However, their transcriptional regulatory roles in the context of leukemia remain unclear. Here, we find that KDM5B is strongly expressed in normal CD34+ hematopoietic stem/progenitor cells and chronic myeloid leukemia (CML) cells. Knockdown of KDM5B in K562 CML cells reduced leukemia colony-forming potential. Transcriptome profiling of KDM5B knockdown K562 cells revealed the deregulation of genes involved in myeloid differentiation and Toll-like receptor signaling. Through the integration of transcriptome and ChIP-seq profiling data, we show that KDM5B is enriched at the binding sites of the GATA and AP-1 transcription factor families, suggesting their collaborations in the regulation of transcription. Even though the binding of KDM5B substantially overlapped with H3K4me1 or H3K4me3 mark at gene promoters, only a small subset of the KDM5B targets showed differential expression in association with the histone demethylation activity. By characterizing the interacting proteins in K562 cells, we discovered that KDM5B recruits protein complexes involved in the mRNA processing machinery, implying an alternative epigenetic action mediated by KDM5B in gene regulation. Our study highlights the oncogenic functions of KDM5B in CML cells and suggests that KDM5B is vital to the transcriptional regulation via multiple epigenetic mechanisms. |
| Databáze: | OpenAIRE |
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