Low-dose histone deacetylase inhibitor treatment leads to tumor growth arrest and multi-lineage differentiation of malignant rhabdoid tumors

Andrea Muscat, Dean Popovski, W. Samantha N. Jayasekara, Fernando J. Rossello, Melissa Ferguson, Kieren D. Marini, Muhammad Alamgeer, Elizabeth M. Algar, Peter Downie, D. Neil Watkins, Jason E. Cain, David Ashley

Research output: Contribution to journalArticleResearchpeer-review

Abstract

Purpose: Malignant rhabdoid tumor (MRT) and atypical teratoid rhabdoid tumors (ATRT) are rare aggressive undifferentiated tumors primarily affecting the kidney and CNS of infants and young children. MRT are almost exclusively characterized by homozygous deletion or inactivation of the chromatin remodeling gene SMARCB1. SMARCB1 protein loss leads to direct impairment of chromatin remodeling and we have previously reported a role for this protein in histone acetylation. This provided the rationale for investigating the therapeutic potential of histone deactylase inhibitors (HDACi) in MRT. Experimental Design: Whereas previously HDACis have been used at doses and schedules that induce cytotoxicity, in the current studies we have tested the hypothesis, both in vitro and in vivo, that sustained treatment of human MRT with lowdose HDACi can lead to sustained cell growth arrest and differentiation. Results: Sustained low-dose panobinostat (LBH589) treatment led to changes in cellular morphology associated with a marked increase in the induction of neural, renal, and osteoblast differentiation pathways. Genome-wide transcriptional profiling highlighted differential gene expression supporting multilineage differentiation. Using mouse xenograft models, sustained lowdose LBH589 treatment caused tumor growth arrest associated with tumor calcification detectable by X-ray imaging. Histological analysis of LBH589-treated tumors revealed significant regions of ossification, confirmed by Alizarin Red staining. Immunohistochemical analysis showed increased TUJ1 and PAX2 staining suggestive of neuronal and renal differentiation, respectively. Conclusions: Low-dose HDACi treatment can terminally differentiate MRT tumor cells and reduce their ability to self-renew. The use of low-dose HDACi as a novel therapeutic approach warrants further investigation.

Original languageEnglish
Pages (from-to)3560-3570
Number of pages11
JournalClinical Cancer Research
Volume22
Issue number14
DOIs
Publication statusPublished - 15 Jul 2016

Cite this

Muscat, Andrea ; Popovski, Dean ; Jayasekara, W. Samantha N. ; Rossello, Fernando J. ; Ferguson, Melissa ; Marini, Kieren D. ; Alamgeer, Muhammad ; Algar, Elizabeth M. ; Downie, Peter ; Watkins, D. Neil ; Cain, Jason E. ; Ashley, David. / Low-dose histone deacetylase inhibitor treatment leads to tumor growth arrest and multi-lineage differentiation of malignant rhabdoid tumors. In: Clinical Cancer Research. 2016 ; Vol. 22, No. 14. pp. 3560-3570.
@article{07565124292b4ab7a725e29a2a316b38,
title = "Low-dose histone deacetylase inhibitor treatment leads to tumor growth arrest and multi-lineage differentiation of malignant rhabdoid tumors",
abstract = "Purpose: Malignant rhabdoid tumor (MRT) and atypical teratoid rhabdoid tumors (ATRT) are rare aggressive undifferentiated tumors primarily affecting the kidney and CNS of infants and young children. MRT are almost exclusively characterized by homozygous deletion or inactivation of the chromatin remodeling gene SMARCB1. SMARCB1 protein loss leads to direct impairment of chromatin remodeling and we have previously reported a role for this protein in histone acetylation. This provided the rationale for investigating the therapeutic potential of histone deactylase inhibitors (HDACi) in MRT. Experimental Design: Whereas previously HDACis have been used at doses and schedules that induce cytotoxicity, in the current studies we have tested the hypothesis, both in vitro and in vivo, that sustained treatment of human MRT with lowdose HDACi can lead to sustained cell growth arrest and differentiation. Results: Sustained low-dose panobinostat (LBH589) treatment led to changes in cellular morphology associated with a marked increase in the induction of neural, renal, and osteoblast differentiation pathways. Genome-wide transcriptional profiling highlighted differential gene expression supporting multilineage differentiation. Using mouse xenograft models, sustained lowdose LBH589 treatment caused tumor growth arrest associated with tumor calcification detectable by X-ray imaging. Histological analysis of LBH589-treated tumors revealed significant regions of ossification, confirmed by Alizarin Red staining. Immunohistochemical analysis showed increased TUJ1 and PAX2 staining suggestive of neuronal and renal differentiation, respectively. Conclusions: Low-dose HDACi treatment can terminally differentiate MRT tumor cells and reduce their ability to self-renew. The use of low-dose HDACi as a novel therapeutic approach warrants further investigation.",
author = "Andrea Muscat and Dean Popovski and Jayasekara, {W. Samantha N.} and Rossello, {Fernando J.} and Melissa Ferguson and Marini, {Kieren D.} and Muhammad Alamgeer and Algar, {Elizabeth M.} and Peter Downie and Watkins, {D. Neil} and Cain, {Jason E.} and David Ashley",
year = "2016",
month = "7",
day = "15",
doi = "10.1158/1078-0432.CCR-15-2260",
language = "English",
volume = "22",
pages = "3560--3570",
journal = "Clinical Cancer Research",
issn = "1078-0432",
publisher = "American Association for Cancer Research",
number = "14",

}

Low-dose histone deacetylase inhibitor treatment leads to tumor growth arrest and multi-lineage differentiation of malignant rhabdoid tumors. / Muscat, Andrea; Popovski, Dean; Jayasekara, W. Samantha N.; Rossello, Fernando J.; Ferguson, Melissa; Marini, Kieren D.; Alamgeer, Muhammad; Algar, Elizabeth M.; Downie, Peter; Watkins, D. Neil; Cain, Jason E.; Ashley, David.

In: Clinical Cancer Research, Vol. 22, No. 14, 15.07.2016, p. 3560-3570.

Research output: Contribution to journalArticleResearchpeer-review

TY - JOUR

T1 - Low-dose histone deacetylase inhibitor treatment leads to tumor growth arrest and multi-lineage differentiation of malignant rhabdoid tumors

AU - Muscat, Andrea

AU - Popovski, Dean

AU - Jayasekara, W. Samantha N.

AU - Rossello, Fernando J.

AU - Ferguson, Melissa

AU - Marini, Kieren D.

AU - Alamgeer, Muhammad

AU - Algar, Elizabeth M.

AU - Downie, Peter

AU - Watkins, D. Neil

AU - Cain, Jason E.

AU - Ashley, David

PY - 2016/7/15

Y1 - 2016/7/15

N2 - Purpose: Malignant rhabdoid tumor (MRT) and atypical teratoid rhabdoid tumors (ATRT) are rare aggressive undifferentiated tumors primarily affecting the kidney and CNS of infants and young children. MRT are almost exclusively characterized by homozygous deletion or inactivation of the chromatin remodeling gene SMARCB1. SMARCB1 protein loss leads to direct impairment of chromatin remodeling and we have previously reported a role for this protein in histone acetylation. This provided the rationale for investigating the therapeutic potential of histone deactylase inhibitors (HDACi) in MRT. Experimental Design: Whereas previously HDACis have been used at doses and schedules that induce cytotoxicity, in the current studies we have tested the hypothesis, both in vitro and in vivo, that sustained treatment of human MRT with lowdose HDACi can lead to sustained cell growth arrest and differentiation. Results: Sustained low-dose panobinostat (LBH589) treatment led to changes in cellular morphology associated with a marked increase in the induction of neural, renal, and osteoblast differentiation pathways. Genome-wide transcriptional profiling highlighted differential gene expression supporting multilineage differentiation. Using mouse xenograft models, sustained lowdose LBH589 treatment caused tumor growth arrest associated with tumor calcification detectable by X-ray imaging. Histological analysis of LBH589-treated tumors revealed significant regions of ossification, confirmed by Alizarin Red staining. Immunohistochemical analysis showed increased TUJ1 and PAX2 staining suggestive of neuronal and renal differentiation, respectively. Conclusions: Low-dose HDACi treatment can terminally differentiate MRT tumor cells and reduce their ability to self-renew. The use of low-dose HDACi as a novel therapeutic approach warrants further investigation.

AB - Purpose: Malignant rhabdoid tumor (MRT) and atypical teratoid rhabdoid tumors (ATRT) are rare aggressive undifferentiated tumors primarily affecting the kidney and CNS of infants and young children. MRT are almost exclusively characterized by homozygous deletion or inactivation of the chromatin remodeling gene SMARCB1. SMARCB1 protein loss leads to direct impairment of chromatin remodeling and we have previously reported a role for this protein in histone acetylation. This provided the rationale for investigating the therapeutic potential of histone deactylase inhibitors (HDACi) in MRT. Experimental Design: Whereas previously HDACis have been used at doses and schedules that induce cytotoxicity, in the current studies we have tested the hypothesis, both in vitro and in vivo, that sustained treatment of human MRT with lowdose HDACi can lead to sustained cell growth arrest and differentiation. Results: Sustained low-dose panobinostat (LBH589) treatment led to changes in cellular morphology associated with a marked increase in the induction of neural, renal, and osteoblast differentiation pathways. Genome-wide transcriptional profiling highlighted differential gene expression supporting multilineage differentiation. Using mouse xenograft models, sustained lowdose LBH589 treatment caused tumor growth arrest associated with tumor calcification detectable by X-ray imaging. Histological analysis of LBH589-treated tumors revealed significant regions of ossification, confirmed by Alizarin Red staining. Immunohistochemical analysis showed increased TUJ1 and PAX2 staining suggestive of neuronal and renal differentiation, respectively. Conclusions: Low-dose HDACi treatment can terminally differentiate MRT tumor cells and reduce their ability to self-renew. The use of low-dose HDACi as a novel therapeutic approach warrants further investigation.

UR - http://www.scopus.com/inward/record.url?scp=84978519600&partnerID=8YFLogxK

U2 - 10.1158/1078-0432.CCR-15-2260

DO - 10.1158/1078-0432.CCR-15-2260

M3 - Article

VL - 22

SP - 3560

EP - 3570

JO - Clinical Cancer Research

JF - Clinical Cancer Research

SN - 1078-0432

IS - 14

ER -