Histone Deacetylase Inhibitors as a Therapeutic Strategy to Eliminate Neoplastic "Stromal" Cells from Giant Cell Tumors of Bone

Sanne Venneker; Robin van Eenige; Alwine B Kruisselbrink; Ieva Palubeckaitė; Alice E Taliento; Inge H Briaire-de Bruijn; Pancras C W Hogendoorn; Michiel A J van de Sande; Hans Gelderblom; Hailiang Mei; Judith V M G Bovée; Karoly Szuhai

doi:10.3390/cancers14194708

Histone Deacetylase Inhibitors as a Therapeutic Strategy to Eliminate Neoplastic "Stromal" Cells from Giant Cell Tumors of Bone

Cancers (Basel). 2022 Sep 27;14(19):4708. doi: 10.3390/cancers14194708.

Affiliations

¹ Department of Pathology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
² Department of Cell and Chemical Biology, Leiden University Medical Center, 2333 ZC Leiden, The Netherlands.
³ Department of Orthopedic Surgery, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
⁴ Department of Medical Oncology, Leiden University Medical Center, 2333 ZA Leiden, The Netherlands.
⁵ Sequencing Analysis Support Core (SASC), Leiden University Medical Center, 2333 ZC Leiden, The Netherlands.

Abstract

The neoplastic "stromal" cells in giant cell tumor of bone (GCTB) harbor a mutation in the H3F3A gene, which causes alterations in the epigenome. Current systemic targeted therapies, such as denosumab, do not affect the neoplastic cells, resulting in relapse upon treatment discontinuation. Therefore, this study examined whether targeting the epigenome could eliminate the neoplastic cells from GCTB. We established four novel cell lines of neoplastic "stromal" cells that expressed the H3F3A p.G34W mutation. These cell lines were used to perform an epigenetics compound screen (n = 128), which identified histone deacetylase (HDAC) inhibitors as key epigenetic regulators in the neoplastic cells. Transcriptome analysis revealed that the neoplastic cells expressed all HDAC isoforms, except for HDAC4. Therefore, five HDAC inhibitors targeting different HDAC subtypes were selected for further studies. All GCTB cell lines were very sensitive to HDAC inhibition in both 2D and 3D in vitro models, and inductions in histone acetylation, as well as apoptosis, were observed. Thus, HDAC inhibition may represent a promising therapeutic strategy to eliminate the neoplastic cells from GCTB lesions, which remains the paramount objective for GCTB patients who require life-long treatment with denosumab.

Keywords: H3F3A; bone neoplasm; epigenetics; giant cell tumor of bone; histone H3.3 variants; histone deacetylase; panobinostat; romidepsin.

Grants and funding

Establishment of the cell lines was financially supported by EuroSarc (EU project FP7-HEALTH-2011-two-stage, Project ID 278742) and RNA sequencing was financially supported by EIT Health (Rare Cancer Programme, Project ID 17527).