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

Abstract

IntroductionHDAC 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.MethodsFour 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.ResultsHDAC8i 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.ConclusionsMPNST 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.

Loss of H3K27 tri-methylation is a diagnostic marker for malignant peripheral nerve sheath tumors and an indicator for an inferior survival

“…In a study performed within malignant peripheral nerve sheath tumor cell lines, histone deacetylase 8 specific inhibitor induced cell growth inhibition and marked S-phase cell cycle arrest. (22) However, resistance to histone deacetylase inhibitors has also been shown in malignant peripheral nerve sheath tumors (23) and likely mutations in chromatin remodelling genes like SUZ12 or EED and thus H3K27 tri-methylation, play a mechanistic role in level of response to histone deacetylase inhibitors. This is an important area for more preclinical modeling.…”

HDACs and HDAC Inhibitors in Cancer Development and Therapy

“…Mechanistically, PLCγ1-dependent calcium mobilization from the endoplasmic reticulum (ER) and in turn release of cytochrome c from mitochondria might contribute to PCI-34051-induced cell death (Balasubramanian et al 2008). Besides T-cell leukemia and lymphoma, human and murine-derived malignant peripheral nerve sheath tumors (MPNST) cells also exhibited “sensitivity” to HDAC8 inhibitors: PCI-34051 and its variant PCI-48012 (Lopez et al 2015). HDAC8 inhibition induced S-phase cell cycle arrest and apoptosis in MPNST cells, but the underlying mechanism remains unclear.…”

Therapeutic applications of histone deacetylase inhibitors in sarcoma

“…Two new HDIs, PCI-34051 and PCI-48012, specifically inhibited the activity of HDAC 8 leading to marked S-phase cell cycle arrest in human malignant peripheral nerve sheath tumors cells 61 . In osteosarcoma, vorinostat arrested the cell cycle in G1 and G2/M phase, while HDI sodium butyrate arrested the cell cycle in G2/M phase 62 .…”