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Effect of caboznatinib on transcriptome and signaling pathways in leukemic cell line K562

ABSTRACT: To identify molecular effects of the tyrosine kinase inhibitor cabozantinib (XL184), we applied gene expression profiling in human erythroid leukemic cell lines K562 using Whole Transcriptome Shotgun Sequencing (RNA-seq). After K562 cell were treated with 1uM cabozantinib for 48 h, differentially expressed genes (DEGs) of 241 genes upregulated and 569 were downregulated were found compared with vehicle group. Up-regulated genes enriched in erythroid maturation associated pathways, such as heme metabolism, transcription factor GATA1 targets, and globin synthesis, while those genes downregulated after expose to cabozantinib were enriched in pathways involved in cell proliferation and cell survival function.

ORGANISM(S): Homo sapiens

PROVIDER: GSE151003 | GEO | 2021/05/21

REPOSITORIES: GEO

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Project description:We previously characterized zinc finger protein gene HZF1 (ZNF16) and demonstrated its important roles in erythroid and megakaryocytic differentiation of K562 cells by loss-function assay. However its effect in erythroid and megakaryocytic differentiation of hematopoietic stem/progenitor cells (HSPCs) and the mechanisms by which it functions have not been understood. In this study, we detected up-regulation of ZNF16 during erythroid and megakaryocytic differentiation of K562 cells and normal CD34+ HSPCs, and demonstrated that ZNF16 promotes erythroid and megakaryocytic differentiation by gain-of-function and loss-of-function experiments. Gene expression profiling by mRNA array and PCR validation in the K562 transforments with ZNF16 over-expression suggested that cell division cycle-associated 7-like gene (JPO2) and v-kit Hardy-Zuckerman 4 feline sarcoma viral oncogene homolog gene (c-KIT) were among the genes regulated possibly by ZNF16. Luciferase reporter assay and Chromatin Immunoprecipitation demonstrated that ZNF16 binds to JPO2 and c-KIT promoters and inhibits their expression in K562 cells. A significant decrease of JPO2 and c-KIT levels was observed during erythroid and megakaryocytic differentiation of K562 and CD34+ cells. The knockdown of either JPO2 or c-KIT partially rescued the differentiation inhibition caused by ZNF16 knockdown. We also found that ZNF16 inhibits c-KIT/c-Raf/MEK/ERK/c-Jun/HEY1 signal pathways, which finally up-regulated expression of GATA1, a central regulator of erthroid and megakaryocyte differentiation. By lentivirus-mediated gene transfer, we demonstrated that enforced expression and knockdown of ZNF16 in HSPCs down-regulated and up-regulated expression of its targets respectively. Our data collectively demonstrate that ZNF16 promotes erythropoiesis and megakaryocytopoiesis via its regulation on JPO2 and c-KIT. 4 samples are analyzed, H4-1 and H4-2 are two stable K562 transductants with ZNF16 over-expression, PC1 and PC2 are stable control K562 transductants. Stable K562 transductants were obtained for RNA extraction and hybridization on an Illumina HumanHT-12 V4.0 expression beadchipe xpression Array platform.

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Effect of caboznatinib on transcriptome and signaling pathways in leukemic cell line K562

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