HDAC8, A Potential Therapeutic Target for the Treatment of Malignant Peripheral Nerve Sheath Tumors (MPNST).

Abstract

INTRODUCTION:

HDAC isoform-specific inhibitors may improve the therapeutic window while limiting toxicities. Developing inhibitors against class I isoforms poses difficulties as they share high homology among their catalytic sites; however, HDAC8 is structurally unique compared to other class I isoforms. HDAC8 inhibitors are novel compounds and have affinity for class I HDAC isoforms demonstrating anti-cancer effects; little is known about their activity in malignant peripheral nerve sheath tumors (MPNST). Recently, we demonstrated anti-MPNST efficacy of HDAC8i in human and murine-derived MPNST pre-clinical models; we now seek to consider the potential therapeutic inhibition of HDAC8 in MPNST.

METHODS:

Four Human MPNST cell lines, a murine-derived MPNST cell line, and two HDAC8 inhibitors (PCI-34051, PCI-48012; Pharmacyclics, Inc. Sunnyvale, CA) were studied. Proliferation was determined using MTS and clonogenic assays. Effects on cell cycle were determined via PI FACS analysis; effects on apoptosis were determined using Annexin V-PI FACS analysis and cleaved caspase 3 expression. In vivo growth effects of HDAC8i were evaluated using MPNST xenograft models. 2D gel electrophoresis and mass spectrometry were used to identify potential HDAC8 deacetylation substrates.

RESULTS:

HDAC8i induced cell growth inhibition and marked S-phase cell cycle arrest in human and murine-derived MPNST cells. Relative to control, HDAC8i induced apoptosis in both human and murine-derived MPNST cells. HDAC8i exhibited significant effects on MPNST xenograft growth (p=0.001) and tumor weight (p=0.02). Four potential HDAC8 substrate targets were identified using a proteomic approach: PARK7, HMGB1, PGAM1, PRDX6.

CONCLUSIONS:

MPNST is an aggressive sarcoma that is notoriously therapy-resistant, hence the urgent need for improved anti-MPNST therapies. HDAC8 inhibition may be useful for MPNST by improving efficacy while limiting toxicities as compared to pan-HDACis.

• Authors: Gonzalo Lopez, Kate Lynn J Bill, Hemant Kumar Bid, Danielle Braggio, Dylan Constantino, Bethany Prudner, Abeba Zewdu, Kara Batte, Dina Lev, Raphael E Pollock
• Journal: PloS one (PLoS One) Vol. 10 Issue 7 Pg. e0133302 ( 2015) ISSN: 1932-6203 [Electronic] United States
• PMID: 26200462 (Publication Type: Journal Article, Research Support, N.I.H., Extramural)

Chemical References

• Histone Deacetylase Inhibitors
• Neoplasm Proteins
• Repressor Proteins
• HDAC8 protein, human
• HDAC8 protein, mouse
• Histone Deacetylases

Topics

• Animals
• Apoptosis
• Cell Line, Tumor
• Female
• Histone Deacetylase Inhibitors (pharmacology)
• Histone Deacetylases (biosynthesis, genetics)
• Humans
• Mice
• Mice, SCID
• Neoplasm Proteins (antagonists & inhibitors, biosynthesis, genetics)
• Neurilemmoma (drug therapy, enzymology, genetics, pathology)
• Repressor Proteins (antagonists & inhibitors, biosynthesis, genetics)
• Xenograft Model Antitumor Assays