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Histone demethylase RBP2 decreases miR-21 in blast crisis of chronic myeloid leukemia.

Zhou M, Zeng J, Wang X, Wang X, Huang T, Fu Y, Sun T, Jia J, Chen C - Oncotarget (2015)

Bottom Line: In this study, we found that the histone H3 lysine 4 (H3K4) demethylase RBP2 (also called JARID1A and KDM5A) is underexpressed in CML-BP.This in turn activated PDCD4.In conclusion, RBP2 epigenetically downregulated miR-21 in blast transformation of CML.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Qilu Hospital of Shandong University, Jinan, Shandong, P. R. China.

ABSTRACT
Chronic myeloid leukemia in the blastic phase (CML-BP) responds poorly to clinical treatments and is usually fatal. In this study, we found that the histone H3 lysine 4 (H3K4) demethylase RBP2 (also called JARID1A and KDM5A) is underexpressed in CML-BP. The RBP2 histone demethylase stimulates leukemia cell differentiation and inhibits cell proliferation. We identified miR-21 was directly downregulated by RBP2 and found that miR-21 downregulated PDCD4 expression in leukemia cells. By binding to miR-21 promoter and by demethylating of trimethylated H3K4 at the miR-21 locus, RBP2 downregulated miR-21 expression. This in turn activated PDCD4. In conclusion, RBP2 epigenetically downregulated miR-21 in blast transformation of CML.

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PDCD4 promotes cell differentiation and inhibits proliferationqRT-PCR and western blot analysis of the mRNA and protein levels of PDCD4 in (A, B) differentiated cells induced by DMSO and (C, D) induced by ATRA. (E) qRT-PCR analysis of the mRNA expression of PDCD4 with PDCD4 expression plasmid transfection. Data are mean ± SEM of 3 independent experiments. (F) Western blot analysis of the protein level of PDCD4 with PDCD4 expression plasmid transfection. β-actin was a loading control. (G, H) Cell proliferation assay of K562 and HL60 cells with PDCD4 expression plasmid transfection after 24 and 48 h. (I, J) Colony-formation assay of K562 and HL60 cells with PDCD4 expression plasmid transfection at 48 h. The results are from 3 independent experiments. *P< 0.05, **P< 0.01.
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Figure 6: PDCD4 promotes cell differentiation and inhibits proliferationqRT-PCR and western blot analysis of the mRNA and protein levels of PDCD4 in (A, B) differentiated cells induced by DMSO and (C, D) induced by ATRA. (E) qRT-PCR analysis of the mRNA expression of PDCD4 with PDCD4 expression plasmid transfection. Data are mean ± SEM of 3 independent experiments. (F) Western blot analysis of the protein level of PDCD4 with PDCD4 expression plasmid transfection. β-actin was a loading control. (G, H) Cell proliferation assay of K562 and HL60 cells with PDCD4 expression plasmid transfection after 24 and 48 h. (I, J) Colony-formation assay of K562 and HL60 cells with PDCD4 expression plasmid transfection at 48 h. The results are from 3 independent experiments. *P< 0.05, **P< 0.01.

Mentions: K562 and HL60 cells induced to undergo granulocytic differentiation by DMSO or ATRA (Supplemental Figure 1) showed upregulated PDCD4 level (Figure 6A-D). Moreover, with ectopic expression of PDCD4 (Figure 6E, F), K562 and HL60 cells proliferated at a slow rate (Figure 6G, H) and showed impaired colony-formation ability (Figure 6I, J).


Histone demethylase RBP2 decreases miR-21 in blast crisis of chronic myeloid leukemia.

Zhou M, Zeng J, Wang X, Wang X, Huang T, Fu Y, Sun T, Jia J, Chen C - Oncotarget (2015)

PDCD4 promotes cell differentiation and inhibits proliferationqRT-PCR and western blot analysis of the mRNA and protein levels of PDCD4 in (A, B) differentiated cells induced by DMSO and (C, D) induced by ATRA. (E) qRT-PCR analysis of the mRNA expression of PDCD4 with PDCD4 expression plasmid transfection. Data are mean ± SEM of 3 independent experiments. (F) Western blot analysis of the protein level of PDCD4 with PDCD4 expression plasmid transfection. β-actin was a loading control. (G, H) Cell proliferation assay of K562 and HL60 cells with PDCD4 expression plasmid transfection after 24 and 48 h. (I, J) Colony-formation assay of K562 and HL60 cells with PDCD4 expression plasmid transfection at 48 h. The results are from 3 independent experiments. *P< 0.05, **P< 0.01.
© Copyright Policy - open-access
Related In: Results  -  Collection

License
Show All Figures
getmorefigures.php?uid=PMC4359230&req=5

Figure 6: PDCD4 promotes cell differentiation and inhibits proliferationqRT-PCR and western blot analysis of the mRNA and protein levels of PDCD4 in (A, B) differentiated cells induced by DMSO and (C, D) induced by ATRA. (E) qRT-PCR analysis of the mRNA expression of PDCD4 with PDCD4 expression plasmid transfection. Data are mean ± SEM of 3 independent experiments. (F) Western blot analysis of the protein level of PDCD4 with PDCD4 expression plasmid transfection. β-actin was a loading control. (G, H) Cell proliferation assay of K562 and HL60 cells with PDCD4 expression plasmid transfection after 24 and 48 h. (I, J) Colony-formation assay of K562 and HL60 cells with PDCD4 expression plasmid transfection at 48 h. The results are from 3 independent experiments. *P< 0.05, **P< 0.01.
Mentions: K562 and HL60 cells induced to undergo granulocytic differentiation by DMSO or ATRA (Supplemental Figure 1) showed upregulated PDCD4 level (Figure 6A-D). Moreover, with ectopic expression of PDCD4 (Figure 6E, F), K562 and HL60 cells proliferated at a slow rate (Figure 6G, H) and showed impaired colony-formation ability (Figure 6I, J).

Bottom Line: In this study, we found that the histone H3 lysine 4 (H3K4) demethylase RBP2 (also called JARID1A and KDM5A) is underexpressed in CML-BP.This in turn activated PDCD4.In conclusion, RBP2 epigenetically downregulated miR-21 in blast transformation of CML.

View Article: PubMed Central - PubMed

Affiliation: Department of Hematology, Qilu Hospital of Shandong University, Jinan, Shandong, P. R. China.

ABSTRACT
Chronic myeloid leukemia in the blastic phase (CML-BP) responds poorly to clinical treatments and is usually fatal. In this study, we found that the histone H3 lysine 4 (H3K4) demethylase RBP2 (also called JARID1A and KDM5A) is underexpressed in CML-BP. The RBP2 histone demethylase stimulates leukemia cell differentiation and inhibits cell proliferation. We identified miR-21 was directly downregulated by RBP2 and found that miR-21 downregulated PDCD4 expression in leukemia cells. By binding to miR-21 promoter and by demethylating of trimethylated H3K4 at the miR-21 locus, RBP2 downregulated miR-21 expression. This in turn activated PDCD4. In conclusion, RBP2 epigenetically downregulated miR-21 in blast transformation of CML.

Show MeSH
Related in: MedlinePlus