Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer

A E Witt; C-W Lee; T I Lee; D J Azzam; B Wang; C Caslini; F Petrocca; J Grosso; M Jones; E B Cohick; A B Gropper; C Wahlestedt; A L Richardson; R Shiekhattar; R A Young; T A Ince

doi:10.1038/onc.2016.337

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Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer

Journal article

Open access

Peer reviewed

Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer

A E Witt, C-W Lee, T I Lee, D J Azzam, B Wang, C Caslini, F Petrocca, J Grosso, M Jones, E B Cohick, …

Oncogene, Vol.36(12), pp.1707-1720

2017-03-23

DOI: https://doi.org/10.1038/onc.2016.337

PMID: 27694895

Abstract

RNA, Small Interfering - genetics

Histone Deacetylases - genetics

Neoplastic Stem Cells - drug effects

Humans

Histone Deacetylases - metabolism

Drug Discovery

Breast Neoplasms - metabolism

Gene Knockdown Techniques

Genes, Lethal

Ovarian Neoplasms - genetics

Phenotype

Animals

Breast Neoplasms - genetics

Heterografts

Neoplastic Stem Cells - metabolism

Biomarkers

Cell Line, Tumor

Female

Histone Deacetylase Inhibitors - pharmacology

Mice

Ovarian Neoplasms - metabolism

Histone Deacetylase 1 - genetics

Disease Models, Animal

Histone Deacetylase 1 - metabolism

Tumours are comprised of a highly heterogeneous population of cells, of which only a small subset of stem-like cells possess the ability to regenerate tumours in vivo. These cancer stem cells (CSCs) represent a significant clinical challenge as they are resistant to conventional cancer therapies and play essential roles in metastasis and tumour relapse. Despite this realization and great interest in CSCs, it has been difficult to develop CSC-targeted treatments due to our limited understanding of CSC biology. Here, we present evidence that specific histone deacetylases (HDACs) play essential roles in the CSC phenotype. Utilizing a novel CSC model, we discovered that the HDACs, HDAC1 and HDAC7, are specifically over-expressed in CSCs when compared to non-stem-tumour-cells (nsTCs). Furthermore, we determine that HDAC1 and HDAC7 are necessary to maintain CSCs, and that over-expression of HDAC7 is sufficient to augment the CSC phenotype. We also demonstrate that clinically available HDAC inhibitors (HDACi) targeting HDAC1 and HDAC7 can be used to preferentially target CSCs. These results provide actionable insights that can be rapidly translated into CSC-specific therapies.

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Collaboration types: Domestic collaboration
Citation topics: 1 Clinical & Life Sciences; 1.25 Molecular & Cell Biology - Cancer, Autophagy & Apoptosis; 1.25.1461 Histone Deacetylase
Web Of Science research areas: Biochemistry & Molecular Biology; Cell Biology; Genetics & Heredity; Oncology
ESI research areas: Molecular Biology & Genetics

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Title: Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer
Creators: A E Witt - Department of Pathology, Interdisciplinary Stem Cell Institute, Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
C-W Lee - Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
T I Lee - The Whitehead Institute for Biomedical Research, Cambridge, MA, USA
D J Azzam - Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL, USA
B Wang - Department of Pathology, Interdisciplinary Stem Cell Institute, Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
C Caslini - Department of Pathology, Interdisciplinary Stem Cell Institute, Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
F Petrocca - Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA
J Grosso - Department of Pathology, Interdisciplinary Stem Cell Institute, Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
M Jones - Department of Pathology, Interdisciplinary Stem Cell Institute, Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
E B Cohick - The Whitehead Institute for Biomedical Research, Cambridge, MA, USA
A B Gropper - The Whitehead Institute for Biomedical Research, Cambridge, MA, USA
C Wahlestedt - Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL, USA
A L Richardson - Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA
R Shiekhattar - Department of Human Genetics, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Biomedical Research Building, Miami, Florida, USA
R A Young - The Whitehead Institute for Biomedical Research, Cambridge, MA, USA
T A Ince - Department of Pathology, Interdisciplinary Stem Cell Institute, Braman Family Breast Cancer Institute, Sylvester Comprehensive Cancer Center, Miller School of Medicine, University of Miami, Miami, FL, USA
Publication Details: Oncogene, Vol.36(12), pp.1707-1720
Publisher: England
Grant note: K22 CA184244 / NCI NIH HHS R01 GM105754 / NIGMS NIH HHS R01 CA146445 / NCI NIH HHS P30 CA010815 / NCI NIH HHS R01 GM078455 / NIGMS NIH HHS
Academic Unit: Miller School of Medicine; UMMG Department of Pathology; UMMG Dept of Human Genetics - Clinical and Translational Genetics; UMMG Dept of Human Genetics (Dr. John T. Macdonald Foundation); UMMG Dept of Psychiatry & Behavioral Sciences
Language: English
Resource Type: Journal article
PMID: 27694895
Record Identifier: 991031576607402976