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Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2

IKAROS, encoded by the IKZF1 gene, is a DNA-binding protein that functions as a tumor suppressor in T cell acute lymphoblastic leukemia (T-ALL). Recent studies have identified IKAROS’s novel function in the epigenetic regulation of gene expression in T-ALL and uncovered many genes that are likely to...

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Autores principales: Dovat, Elanora, Song, Chunhua, Hu, Tommy, Rahman, Mohammad Atiqur, Dhanyamraju, Pavan Kumar, Klink, Morgann, Bogush, Daniel, Soliman, Mario, Kane, Shriya, McGrath, Mary, Ding, Yali, Desai, Dhimant, Sharma, Arati, Gowda, Chandrika
Formato: Online Artículo Texto
Lenguaje:English
Publicado: MDPI 2021
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830534/
https://www.ncbi.nlm.nih.gov/pubmed/33467550
http://dx.doi.org/10.3390/ijms22020819
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author Dovat, Elanora
Song, Chunhua
Hu, Tommy
Rahman, Mohammad Atiqur
Dhanyamraju, Pavan Kumar
Klink, Morgann
Bogush, Daniel
Soliman, Mario
Kane, Shriya
McGrath, Mary
Ding, Yali
Desai, Dhimant
Sharma, Arati
Gowda, Chandrika
author_facet Dovat, Elanora
Song, Chunhua
Hu, Tommy
Rahman, Mohammad Atiqur
Dhanyamraju, Pavan Kumar
Klink, Morgann
Bogush, Daniel
Soliman, Mario
Kane, Shriya
McGrath, Mary
Ding, Yali
Desai, Dhimant
Sharma, Arati
Gowda, Chandrika
author_sort Dovat, Elanora
collection PubMed
description IKAROS, encoded by the IKZF1 gene, is a DNA-binding protein that functions as a tumor suppressor in T cell acute lymphoblastic leukemia (T-ALL). Recent studies have identified IKAROS’s novel function in the epigenetic regulation of gene expression in T-ALL and uncovered many genes that are likely to be directly regulated by IKAROS. Here, we report the transcriptional regulation of two genes, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) and phosphoinositide kinase, FYVE-type zinc finger containing (PIKFYVE), by IKAROS in T-ALL. PIK3CD encodes the protein p110δ subunit of phosphoinositide 3-kinase (PI3K). The PI3K/AKT pathway is frequently dysregulated in cancers, including T-ALL. IKAROS binds to the promoter regions of PIK3CD and PIKFYVE and reduces their transcription in primary T-ALL. Functional analysis demonstrates that IKAROS functions as a transcriptional repressor of both PIK3CD and PIKFYVE. Protein kinase CK2 (CK2) is a pro-oncogenic kinase that is overexpressed in T-ALL. CK2 phosphorylates IKAROS, impairs IKAROS’s DNA-binding ability, and functions as a repressor of PIK3CD and PIKFYVE. CK2 inhibition results in increased IKAROS binding to the promoters of PIK3CD and PIKFYVE and the transcriptional repression of both these genes. Overall, the presented data demonstrate for the first time that in T-ALL, CK2 hyperactivity contributes to PI3K signaling pathway upregulation, at least in part, through impaired IKAROS transcriptional regulation of PIK3CD and PIKFYVE. Targeting CK2 restores IKAROS’s regulatory effects on the PI3K oncogenic signaling pathway.
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spelling pubmed-78305342021-01-26 Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2 Dovat, Elanora Song, Chunhua Hu, Tommy Rahman, Mohammad Atiqur Dhanyamraju, Pavan Kumar Klink, Morgann Bogush, Daniel Soliman, Mario Kane, Shriya McGrath, Mary Ding, Yali Desai, Dhimant Sharma, Arati Gowda, Chandrika Int J Mol Sci Article IKAROS, encoded by the IKZF1 gene, is a DNA-binding protein that functions as a tumor suppressor in T cell acute lymphoblastic leukemia (T-ALL). Recent studies have identified IKAROS’s novel function in the epigenetic regulation of gene expression in T-ALL and uncovered many genes that are likely to be directly regulated by IKAROS. Here, we report the transcriptional regulation of two genes, phosphatidylinositol-4,5-bisphosphate 3-kinase catalytic subunit delta (PIK3CD) and phosphoinositide kinase, FYVE-type zinc finger containing (PIKFYVE), by IKAROS in T-ALL. PIK3CD encodes the protein p110δ subunit of phosphoinositide 3-kinase (PI3K). The PI3K/AKT pathway is frequently dysregulated in cancers, including T-ALL. IKAROS binds to the promoter regions of PIK3CD and PIKFYVE and reduces their transcription in primary T-ALL. Functional analysis demonstrates that IKAROS functions as a transcriptional repressor of both PIK3CD and PIKFYVE. Protein kinase CK2 (CK2) is a pro-oncogenic kinase that is overexpressed in T-ALL. CK2 phosphorylates IKAROS, impairs IKAROS’s DNA-binding ability, and functions as a repressor of PIK3CD and PIKFYVE. CK2 inhibition results in increased IKAROS binding to the promoters of PIK3CD and PIKFYVE and the transcriptional repression of both these genes. Overall, the presented data demonstrate for the first time that in T-ALL, CK2 hyperactivity contributes to PI3K signaling pathway upregulation, at least in part, through impaired IKAROS transcriptional regulation of PIK3CD and PIKFYVE. Targeting CK2 restores IKAROS’s regulatory effects on the PI3K oncogenic signaling pathway. MDPI 2021-01-15 /pmc/articles/PMC7830534/ /pubmed/33467550 http://dx.doi.org/10.3390/ijms22020819 Text en © 2021 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (http://creativecommons.org/licenses/by/4.0/).
spellingShingle Article
Dovat, Elanora
Song, Chunhua
Hu, Tommy
Rahman, Mohammad Atiqur
Dhanyamraju, Pavan Kumar
Klink, Morgann
Bogush, Daniel
Soliman, Mario
Kane, Shriya
McGrath, Mary
Ding, Yali
Desai, Dhimant
Sharma, Arati
Gowda, Chandrika
Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2
title Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2
title_full Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2
title_fullStr Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2
title_full_unstemmed Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2
title_short Transcriptional Regulation of PIK3CD and PIKFYVE in T-Cell Acute Lymphoblastic Leukemia by IKAROS and Protein Kinase CK2
title_sort transcriptional regulation of pik3cd and pikfyve in t-cell acute lymphoblastic leukemia by ikaros and protein kinase ck2
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7830534/
https://www.ncbi.nlm.nih.gov/pubmed/33467550
http://dx.doi.org/10.3390/ijms22020819
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