Inhibition of Plk1 and Cyclin B1 expression results in panobinostat-induced G(2) delay and mitotic defects

Michael Prystowsky; Katherine Feeney; Nicole Kawachi; Cristina Montagna; Michelle Willmott; Christopher Wasson; Maciej Antkowiak; Olivier Loudig; Joanna Parish

doi:10.1038/srep02640

Inhibition of Plk1 and Cyclin B1 expression results in panobinostat-induced G(2) delay and mitotic defects

Michael Prystowsky, Katherine Feeney, Nicole Kawachi, Cristina Montagna, Michelle Willmott, Christopher Wasson, Maciej Antkowiak, Olivier Loudig, Joanna Parish^*

^*Corresponding author for this work

School of Medicine

Research output: Contribution to journal › Article › peer-review

Abstract

The development of clinically useful histone deacetylase inhibitors has expanded greatly. In a preclinical study, we showed that panobinostat (LBH589) inhibits cell cycle progression of human head and neck squamous cell carcinoma (HNSCC) cell lines at G(2)/M and an associated decrease in expression of particular genes required for passage through G(2) and mitosis. In this study we sought to analyse the mechanistic underpinnings of panobinostat-induced growth arrest. HNSCC cell lines were synchronised and progression through mitosis monitored. We demonstrate that panobinostat causes a marked G(2) delay and mitotic defects. A loss of G(2)-specific Plk1 and Cyclin B1 expression and co-incident increase in p21(Waf1/Cip1) expression is also shown. Furthermore, we show a significant loss of E2F1 recruitment to the promoters of these genes in response to panobinostat treatment. These data provide mechanistic evidence of panobinostat-induced cell cycle arrest and highlight its potential as a chemotherapeutic agent for HNSCC.

Original language	English
Article number	e2640
Number of pages	10
Journal	Scientific Reports
Volume	3
DOIs	https://doi.org/10.1038/srep02640
Publication status	Published - 12 Sept 2013

Keywords

Histone deacetylase inhibitor
Carcinoma-cell lines
Gene-expression
Cancer cells
In-vitro
LBH589
Apoptosis
Polo
Head
P53

UN SDGs

This output contributes to the following UN Sustainable Development Goals (SDGs)

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Antkowiak_2013_SR_Inhibition
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title = "Inhibition of Plk1 and Cyclin B1 expression results in panobinostat-induced G(2) delay and mitotic defects",

abstract = "The development of clinically useful histone deacetylase inhibitors has expanded greatly. In a preclinical study, we showed that panobinostat (LBH589) inhibits cell cycle progression of human head and neck squamous cell carcinoma (HNSCC) cell lines at G(2)/M and an associated decrease in expression of particular genes required for passage through G(2) and mitosis. In this study we sought to analyse the mechanistic underpinnings of panobinostat-induced growth arrest. HNSCC cell lines were synchronised and progression through mitosis monitored. We demonstrate that panobinostat causes a marked G(2) delay and mitotic defects. A loss of G(2)-specific Plk1 and Cyclin B1 expression and co-incident increase in p21(Waf1/Cip1) expression is also shown. Furthermore, we show a significant loss of E2F1 recruitment to the promoters of these genes in response to panobinostat treatment. These data provide mechanistic evidence of panobinostat-induced cell cycle arrest and highlight its potential as a chemotherapeutic agent for HNSCC.",

keywords = "Histone deacetylase inhibitor, Carcinoma-cell lines, Gene-expression, Cancer cells, In-vitro, LBH589, Apoptosis, Polo, Head, P53",

author = "Michael Prystowsky and Katherine Feeney and Nicole Kawachi and Cristina Montagna and Michelle Willmott and Christopher Wasson and Maciej Antkowiak and Olivier Loudig and Joanna Parish",

note = "Work by JP is funded by a Royal Society University Research Fellowship award. Experiments carried out by MBP were supported by the Department of Pathology, Albert Einstein College of Medicine / Montefiore Medical Center.",

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T1 - Inhibition of Plk1 and Cyclin B1 expression results in panobinostat-induced G(2) delay and mitotic defects

AU - Prystowsky, Michael

AU - Feeney, Katherine

AU - Kawachi, Nicole

AU - Montagna, Cristina

AU - Willmott, Michelle

AU - Wasson, Christopher

AU - Antkowiak, Maciej

AU - Loudig, Olivier

AU - Parish, Joanna

N1 - Work by JP is funded by a Royal Society University Research Fellowship award. Experiments carried out by MBP were supported by the Department of Pathology, Albert Einstein College of Medicine / Montefiore Medical Center.

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N2 - The development of clinically useful histone deacetylase inhibitors has expanded greatly. In a preclinical study, we showed that panobinostat (LBH589) inhibits cell cycle progression of human head and neck squamous cell carcinoma (HNSCC) cell lines at G(2)/M and an associated decrease in expression of particular genes required for passage through G(2) and mitosis. In this study we sought to analyse the mechanistic underpinnings of panobinostat-induced growth arrest. HNSCC cell lines were synchronised and progression through mitosis monitored. We demonstrate that panobinostat causes a marked G(2) delay and mitotic defects. A loss of G(2)-specific Plk1 and Cyclin B1 expression and co-incident increase in p21(Waf1/Cip1) expression is also shown. Furthermore, we show a significant loss of E2F1 recruitment to the promoters of these genes in response to panobinostat treatment. These data provide mechanistic evidence of panobinostat-induced cell cycle arrest and highlight its potential as a chemotherapeutic agent for HNSCC.

AB - The development of clinically useful histone deacetylase inhibitors has expanded greatly. In a preclinical study, we showed that panobinostat (LBH589) inhibits cell cycle progression of human head and neck squamous cell carcinoma (HNSCC) cell lines at G(2)/M and an associated decrease in expression of particular genes required for passage through G(2) and mitosis. In this study we sought to analyse the mechanistic underpinnings of panobinostat-induced growth arrest. HNSCC cell lines were synchronised and progression through mitosis monitored. We demonstrate that panobinostat causes a marked G(2) delay and mitotic defects. A loss of G(2)-specific Plk1 and Cyclin B1 expression and co-incident increase in p21(Waf1/Cip1) expression is also shown. Furthermore, we show a significant loss of E2F1 recruitment to the promoters of these genes in response to panobinostat treatment. These data provide mechanistic evidence of panobinostat-induced cell cycle arrest and highlight its potential as a chemotherapeutic agent for HNSCC.

KW - Histone deacetylase inhibitor

KW - Carcinoma-cell lines

KW - Gene-expression

KW - Cancer cells

KW - In-vitro

KW - LBH589

KW - Apoptosis

KW - Polo

KW - Head

KW - P53

U2 - 10.1038/srep02640

DO - 10.1038/srep02640

M3 - Article

SN - 2045-2322

VL - 3

JO - Scientific Reports

JF - Scientific Reports

M1 - e2640

ER -

Inhibition of Plk1 and Cyclin B1 expression results in panobinostat-induced G(2) delay and mitotic defects

Abstract

Keywords

UN SDGs

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