Identification of a cancer stem cell-specific function for the histone deacetylases, HDAC1 and HDAC7, in breast and ovarian cancer.
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.
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.
A E
AE
Witt
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
C-W
CW
Lee
The Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
T I
TI
Lee
Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL, USA.
D J
DJ
Azzam
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.
B
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
C
Caslini
Program in Cellular and Molecular Medicine, Boston Children's Hospital, Department of Pediatrics, Harvard Medical School, Boston, MA, USA.
F
F
Petrocca
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.
J
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
M
Jones
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.|The Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
E B
EB
Cohick
The Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
A B
AB
Gropper
Department of Psychiatry and Behavioral Sciences, Center for Therapeutic Innovation, University of Miami Miller School of Medicine, Miami, FL, USA.
C
C
Wahlestedt
Department of Pathology, Brigham and Women's Hospital, Harvard Medical School, Boston, MA, USA.
A L
AL
Richardson
Department of Human Genetics, University of Miami Miller School of Medicine, Sylvester Comprehensive Cancer Center, Biomedical Research Building, Miami, Florida, USA.
R
R
Shiekhattar
The Whitehead Institute for Biomedical Research, Cambridge, MA, USA.
R A
RA
Young
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.
T A
TA
Ince
D000818:Animals; D015415:Biomarkers; D001943:Breast Neoplasms / Q000235:genetics / Q000378:metabolism*; D045744:Cell Line, Tumor; D004195:Disease Models, Animal; D055808:Drug Discovery; D005260:Female; D055785:Gene Knockdown Techniques; D005804:Genes, Lethal; D064593:Heterografts; D056284:Histone Deacetylase 1 / Q000235:genetics / Q000378:metabolism*; D056572:Histone Deacetylase Inhibitors / Q000494:pharmacology; D006655:Histone Deacetylases / Q000235:genetics / Q000378:metabolism*; D006801:Humans; D051379:Mice; D014411:Neoplastic Stem Cells / Q000187:drug effects / Q000378:metabolism*; D010051:Ovarian Neoplasms / Q000235:genetics / Q000378:metabolism*; D010641:Phenotype; D034741:RNA, Small Interfering / Q000235:genetics
D015415:Biomarkers; D056572:Histone Deacetylase Inhibitors; D034741:RNA, Small Interfering; C543273:HDAC7 protein, human; D056284:Histone Deacetylase 1; D006655:Histone Deacetylases
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