Abstract 988: Epigenetic upregulation of neuropilin-1 promotes osteosarcoma progression and metastasis

Abstract

Abstract Background: Osteosarcoma (OS) frequently metastasizes to lung and the prognosis for these patients is grim with 5-year overall survival rates as low as 30%. There has been little change in the treatment paradigm for this disease and new targeted therapies are an urgent and unmet clinical need. Previously, we showed that the epigenetic regulators, histone deacetylase 1 and 2 (HDAC1 and 2) are key mediators of OS progression and lung metastasis and that the HDAC1/2 selective inhibitor (romidepsin) significantly prevented OS lung metastasis in vivo. Yet, inhibition of HDACs by romidepsin has noted toxicities in humans and here we define the potential mechanisms through which HDAC1/2 mediate their effects in a bid to identify additional therapeutic targets. Methods: Human OS cell lines were treated with vehicle or romidepsin for 24h before undergoing RNA/protein isolation for microarray/proteomics to identify differentially regulated genes. Standard siRNA, proliferation, migration and molecular analyses were preformed to investigate the role of candidate genes in OS malignant behavior. Results: Microarray/proteomics analyses on romidepsin treated OS cells identified neuropilin-1 (NRP1), a membrane bound co-receptor for vascular endothelial growth factor, to be highly downregulated in response to romidepsin; (<70% compared to vehicle in multiple OS cell lines). NRP1 knockdown (siRNA) led to reduced cell proliferation and interestingly, increased cell migration. Further, a phosphokinase array revealed increased phosphorylation in eNOS, ERK 1/2 and β-catenin in NRP1 knockdown cells that is consistent with a role for NRP1 in regulating OS migration. Based on this data, we hypothesize that NRP1 is a significant regulator of OS proliferation and migration. Our next steps will be to dissect the role of NRP1 silencing in OS invasion and metastasisin vivo and the potential role of NRP1 in OS differentiation. Conclusions: HDAC1/2 contributes to OS growth potentially via the upregulation of NRP1, a therapeutically actionable target. Citation Format: Niveditha Nerlakanti, Jeremy Mcguire, Diana Yu, Damon Reed, Conor C. Lynch. Epigenetic upregulation of neuropilin-1 promotes osteosarcoma progression and metastasis [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 988.