VPA mediates bidirectional regulation of cell cycle progression through the PPP2R2A-Chk1 signaling axis in response to HU.

Su, B; Lim, D; Qi, C; Zhang, Z; Wang, J; Zhang, F; Dong, C; Feng, Z

VPA mediates bidirectional regulation of cell cycle progression through the PPP2R2A-Chk1 signaling axis in response to HU.

Su, B Lim, D Qi, C Zhang, Z Wang, J Zhang, F Dong, C Feng, Z

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Publisher:: SPRINGERNATURE
Publication Type:: Journal Article
Citation:: Cell Death Dis, 2023, 14, (2), pp. 114
Issue Date:: 2023-02-13

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Field	Value	Language
dc.contributor.author	Su, B
dc.contributor.author	Lim, D
dc.contributor.author	Qi, C
dc.contributor.author	Zhang, Z
dc.contributor.author	Wang, J
dc.contributor.author	Zhang, F
dc.contributor.author	Dong, C
dc.contributor.author	Feng, Z
dc.date.accessioned	2023-10-05T00:40:02Z
dc.date.available	2023-02-02
dc.date.available	2023-10-05T00:40:02Z
dc.date.issued	2023-02-13
dc.identifier.citation	Cell Death Dis, 2023, 14, (2), pp. 114
dc.identifier.issn	2041-4889
dc.identifier.issn	2041-4889
dc.identifier.uri	http://hdl.handle.net/10453/172504
dc.description.abstract	Cell cycle checkpoint kinases play a pivotal role in protecting against replicative stress. In this study, valproic acid (VPA), a histone deacetylase inhibitor (HDACi), was found to promote breast cancer MCF-7 cells to traverse into G2/M phase for catastrophic injury by promoting PPP2R2A (the B-regulatory subunit of Phosphatase PP2A) to facilitate the dephosphorylation of Chk1 at Ser317 and Ser345. By contrast, VPA protected normal 16HBE cells from HU toxicity through decreasing PPP2R2A expression and increasing Chk1 phosphorylation. The effect of VPA on PPP2R2A was at the post-transcription level through HDAC1/2. The in vitro results were affirmed in vivo. Patients with lower PPP2R2A expression and higher pChk1 expression showed significantly worse survival. PPP2R2A D197 and N181 are essential for PPP2R2A-Chk1 signaling and VPA-mediated bidirectional effect on augmenting HU-induced tumor cell death and protecting normal cells.
dc.format	Electronic
dc.language	eng
dc.publisher	SPRINGERNATURE
dc.relation.ispartof	Cell Death Dis
dc.relation.isbasedon	10.1038/s41419-023-05649-8
dc.rights	info:eu-repo/semantics/openAccess
dc.subject	0601 Biochemistry and Cell Biology, 1112 Oncology and Carcinogenesis
dc.subject.classification	3101 Biochemistry and cell biology
dc.subject.classification	3211 Oncology and carcinogenesis
dc.subject.mesh	Humans
dc.subject.mesh	Valproic Acid
dc.subject.mesh	Cell Division
dc.subject.mesh	Phosphorylation
dc.subject.mesh	Histone Deacetylase Inhibitors
dc.subject.mesh	DNA Replication
dc.subject.mesh	Cell Cycle
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Protein Phosphatase 2
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Humans
dc.subject.mesh	Valproic Acid
dc.subject.mesh	Cell Cycle
dc.subject.mesh	Cell Division
dc.subject.mesh	DNA Replication
dc.subject.mesh	Phosphorylation
dc.subject.mesh	Protein Phosphatase 2
dc.subject.mesh	Histone Deacetylase Inhibitors
dc.subject.mesh	Humans
dc.subject.mesh	Valproic Acid
dc.subject.mesh	Cell Division
dc.subject.mesh	Phosphorylation
dc.subject.mesh	Histone Deacetylase Inhibitors
dc.subject.mesh	DNA Replication
dc.subject.mesh	Cell Cycle
dc.subject.mesh	Cell Line, Tumor
dc.subject.mesh	Protein Phosphatase 2
dc.title	VPA mediates bidirectional regulation of cell cycle progression through the PPP2R2A-Chk1 signaling axis in response to HU.
dc.type	Journal Article
utslib.citation.volume	14
utslib.location.activity	England
utslib.for	0601 Biochemistry and Cell Biology
utslib.for	1112 Oncology and Carcinogenesis
pubs.organisational-group	/University of Technology Sydney
pubs.organisational-group	/University of Technology Sydney/Faculty of Health
pubs.organisational-group	/University of Technology Sydney/Faculty of Health/IMPACCT
utslib.copyright.status	open_access	*
dc.date.updated	2023-10-05T00:39:51Z
pubs.issue	2
pubs.publication-status	Published online
pubs.volume	14
utslib.citation.issue	2

Abstract:

Cell cycle checkpoint kinases play a pivotal role in protecting against replicative stress. In this study, valproic acid (VPA), a histone deacetylase inhibitor (HDACi), was found to promote breast cancer MCF-7 cells to traverse into G2/M phase for catastrophic injury by promoting PPP2R2A (the B-regulatory subunit of Phosphatase PP2A) to facilitate the dephosphorylation of Chk1 at Ser317 and Ser345. By contrast, VPA protected normal 16HBE cells from HU toxicity through decreasing PPP2R2A expression and increasing Chk1 phosphorylation. The effect of VPA on PPP2R2A was at the post-transcription level through HDAC1/2. The in vitro results were affirmed in vivo. Patients with lower PPP2R2A expression and higher pChk1 expression showed significantly worse survival. PPP2R2A D197 and N181 are essential for PPP2R2A-Chk1 signaling and VPA-mediated bidirectional effect on augmenting HU-induced tumor cell death and protecting normal cells.

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http://hdl.handle.net/10453/172504