Targeting histone deacetylase 3 (HDAC3) in the bone marrow microenvironment inhibits multiple myeloma proliferation by modulating exosomes and IL-6 trans-signaling.
Animals
Bone Marrow
/ metabolism
Cell Proliferation
/ physiology
Endothelial Cells
/ enzymology
Exosomes
/ metabolism
Heterografts
Histone Deacetylases
/ metabolism
Humans
Interleukin-6
/ metabolism
Mesenchymal Stem Cells
/ enzymology
Mice
Multiple Myeloma
/ enzymology
Signal Transduction
/ physiology
Tumor Microenvironment
/ physiology
Journal
Leukemia
ISSN: 1476-5551
Titre abrégé: Leukemia
Pays: England
ID NLM: 8704895
Informations de publication
Date de publication:
01 2020
01 2020
Historique:
received:
08
12
2018
accepted:
17
04
2019
pubmed:
31
5
2019
medline:
2
7
2020
entrez:
31
5
2019
Statut:
ppublish
Résumé
Multiple myeloma (MM) is an incurable cancer that derives pro-survival/proliferative signals from the bone marrow (BM) niche. Novel agents targeting not only cancer cells, but also the BM-niche have shown the greatest activity in MM. Histone deacetylases (HDACs) are therapeutic targets in MM and we previously showed that HDAC3 inhibition decreases MM proliferation both alone and in co-culture with bone marrow stromal cells (BMSC). In this study, we investigate the effects of HDAC3 targeting in BMSCs. Using both BMSC lines as well as patient-derived BMSCs, we show that HDAC3 expression in BMSCs can be induced by co-culture with MM cells. Knock-out (KO), knock-down (KD), and pharmacologic inhibition of HDAC3 in BMSCs results in decreased MM cell proliferation; including in autologous cultures of patient MM cells with BMSCs. We identified both quantitative and qualitative changes in exosomes and exosomal miRNA, as well as inhibition of IL-6 trans-signaling, as molecular mechanisms mediating anti-MM activity. Furthermore, we show that HDAC3-KD in BM endothelial cells decreases neoangiogenesis, consistent with a broad effect of HDAC3 targeting in the BM-niche. Our results therefore support the clinical development of HDAC3 inhibitors based not only on their direct anti-MM effects, but also their modulation of the BM microenvironment.
Identifiants
pubmed: 31142847
doi: 10.1038/s41375-019-0493-x
pii: 10.1038/s41375-019-0493-x
pmc: PMC6883144
mid: NIHMS1527350
doi:
Substances chimiques
Interleukin-6
0
Histone Deacetylases
EC 3.5.1.98
histone deacetylase 3
EC 3.5.1.98
Types de publication
Journal Article
Research Support, N.I.H., Extramural
Research Support, Non-U.S. Gov't
Langues
eng
Sous-ensembles de citation
IM
Pagination
196-209Subventions
Organisme : NCI NIH HHS
ID : R01 CA178264
Pays : United States
Organisme : NCI NIH HHS
ID : P01 CA155258
Pays : United States
Organisme : NCI NIH HHS
ID : R01 CA050947
Pays : United States
Organisme : NCI NIH HHS
ID : P50 CA100707
Pays : United States
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