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AMPK Associates with Chromatin and Phosphorylates the TAF-1 Subunit of the Transcription Initiation Complex to Regulate Histone Gene Expression in ALL Cells

The survival rates for relapsed/refractory acute lymphoblastic leukemia (ALL) remain poor. We and others have reported that ALL cells are vulnerable to conditions inducing energy/ER-stress mediated by AMP-activated protein kinase (AMPK). To identify the target genes directly regulated by AMPKα2, we...

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Autores principales: Sun, Guangyan, Leclerc, Guy J., Chahar, Sanjay, Barredo, Julio C.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: American Association for Cancer Research 2023
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10690046/
https://www.ncbi.nlm.nih.gov/pubmed/37682252
http://dx.doi.org/10.1158/1541-7786.MCR-23-0502
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author Sun, Guangyan
Leclerc, Guy J.
Chahar, Sanjay
Barredo, Julio C.
author_facet Sun, Guangyan
Leclerc, Guy J.
Chahar, Sanjay
Barredo, Julio C.
author_sort Sun, Guangyan
collection PubMed
description The survival rates for relapsed/refractory acute lymphoblastic leukemia (ALL) remain poor. We and others have reported that ALL cells are vulnerable to conditions inducing energy/ER-stress mediated by AMP-activated protein kinase (AMPK). To identify the target genes directly regulated by AMPKα2, we performed genome-wide RNA-seq and ChIP-seq in CCRF-CEM (T-ALL) cells expressing HA-AMPKα2 (CN2) under normal and energy/metabolic stress conditions. CN2 cells show significantly altered AMPKα2 genomic binding and transcriptomic profile under metabolic stress conditions, including reduced histone gene expression. Proteomic analysis and in vitro kinase assays identified the TATA-Box–Binding Protein–Associated Factor 1 (TAF1) as a novel AMPKα2 substrate that downregulates histone gene transcription in response to energy/metabolic stress. Knockdown and knockout studies demonstrated that both AMPKα2 and TAF1 are required for histone gene expression. Mechanistically, upon activation, AMPKα2 phosphorylates TAF1 at Ser-1353 which impairs TAF1 interaction with RNA polymerase II (Pol II), leading to a compromised state of p-AMPKα2/p-TAF1/Pol II chromatin association and suppression of transcription. This mechanism was also observed in primary ALL cells and in vivo in NSG mice. Consequently, we uncovered a non-canonical function of AMPK that phosphorylates TAF1, both members of a putative chromatin-associated transcription complex that regulate histone gene expression, among others, in response to energy/metabolic stress. IMPLICATIONS: Fully delineating the protein interactome by which AMPK regulates adaptive survival responses to energy/metabolic stress, either via epigenetic gene regulation or other mechanisms, will allow the rational development of strategies to overcome de novo or acquired resistance in ALL and other cancers.
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spelling pubmed-106900462023-12-02 AMPK Associates with Chromatin and Phosphorylates the TAF-1 Subunit of the Transcription Initiation Complex to Regulate Histone Gene Expression in ALL Cells Sun, Guangyan Leclerc, Guy J. Chahar, Sanjay Barredo, Julio C. Mol Cancer Res Cancer Genes and Networks The survival rates for relapsed/refractory acute lymphoblastic leukemia (ALL) remain poor. We and others have reported that ALL cells are vulnerable to conditions inducing energy/ER-stress mediated by AMP-activated protein kinase (AMPK). To identify the target genes directly regulated by AMPKα2, we performed genome-wide RNA-seq and ChIP-seq in CCRF-CEM (T-ALL) cells expressing HA-AMPKα2 (CN2) under normal and energy/metabolic stress conditions. CN2 cells show significantly altered AMPKα2 genomic binding and transcriptomic profile under metabolic stress conditions, including reduced histone gene expression. Proteomic analysis and in vitro kinase assays identified the TATA-Box–Binding Protein–Associated Factor 1 (TAF1) as a novel AMPKα2 substrate that downregulates histone gene transcription in response to energy/metabolic stress. Knockdown and knockout studies demonstrated that both AMPKα2 and TAF1 are required for histone gene expression. Mechanistically, upon activation, AMPKα2 phosphorylates TAF1 at Ser-1353 which impairs TAF1 interaction with RNA polymerase II (Pol II), leading to a compromised state of p-AMPKα2/p-TAF1/Pol II chromatin association and suppression of transcription. This mechanism was also observed in primary ALL cells and in vivo in NSG mice. Consequently, we uncovered a non-canonical function of AMPK that phosphorylates TAF1, both members of a putative chromatin-associated transcription complex that regulate histone gene expression, among others, in response to energy/metabolic stress. IMPLICATIONS: Fully delineating the protein interactome by which AMPK regulates adaptive survival responses to energy/metabolic stress, either via epigenetic gene regulation or other mechanisms, will allow the rational development of strategies to overcome de novo or acquired resistance in ALL and other cancers. American Association for Cancer Research 2023-12-01 2023-09-08 /pmc/articles/PMC10690046/ /pubmed/37682252 http://dx.doi.org/10.1158/1541-7786.MCR-23-0502 Text en ©2023 The Authors; Published by the American Association for Cancer Research https://creativecommons.org/licenses/by-nc-nd/4.0/This open access article is distributed under the Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license.
spellingShingle Cancer Genes and Networks
Sun, Guangyan
Leclerc, Guy J.
Chahar, Sanjay
Barredo, Julio C.
AMPK Associates with Chromatin and Phosphorylates the TAF-1 Subunit of the Transcription Initiation Complex to Regulate Histone Gene Expression in ALL Cells
title AMPK Associates with Chromatin and Phosphorylates the TAF-1 Subunit of the Transcription Initiation Complex to Regulate Histone Gene Expression in ALL Cells
title_full AMPK Associates with Chromatin and Phosphorylates the TAF-1 Subunit of the Transcription Initiation Complex to Regulate Histone Gene Expression in ALL Cells
title_fullStr AMPK Associates with Chromatin and Phosphorylates the TAF-1 Subunit of the Transcription Initiation Complex to Regulate Histone Gene Expression in ALL Cells
title_full_unstemmed AMPK Associates with Chromatin and Phosphorylates the TAF-1 Subunit of the Transcription Initiation Complex to Regulate Histone Gene Expression in ALL Cells
title_short AMPK Associates with Chromatin and Phosphorylates the TAF-1 Subunit of the Transcription Initiation Complex to Regulate Histone Gene Expression in ALL Cells
title_sort ampk associates with chromatin and phosphorylates the taf-1 subunit of the transcription initiation complex to regulate histone gene expression in all cells
topic Cancer Genes and Networks
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10690046/
https://www.ncbi.nlm.nih.gov/pubmed/37682252
http://dx.doi.org/10.1158/1541-7786.MCR-23-0502
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