Abstract 2917: Antitumor effects of an epigenetic inhibitor, 4SC-202, on human osteosarcoma cells

• Published in: Cancer research (Chicago, Ill.) Ill.), 2020-08, Vol.80 (16_Supplement), p.2917-2917
• Main Authors: Torres, Haydee Magdalena, Van Cleave, Ashley, Palmer, Mykayla, Callahan, Dakota, Smithback, Austyn, May, Danielle, Roux, Kyle, Tao, Jianning
• Format: Article
• Language: English
• ISSN: 0008-5472; 1538-7445
• DOI: 10.1158/1538-7445.AM2020-2917

Comprising of 2% of all childhood cancers, osteosarcoma (OS) is the most common primary bone cancer and occurs spontaneously in the skeleton, mostly in the long bones of the extremities near the metaphysical growth plates. In addition to social and emotional consequences of undergoing the rigor of OS treatment, approximately 20% of OS patients show radiographically demonstrable metastasis at initial diagnosis, and 30-40% eventually develop metastatic disease, typically to the lungs. Drug resistance to current therapy together with severe side effects urgently calls for alternative treatment strategies targeting critical cancer signaling pathways. Recently, our and other studies suggest that hyperactivation of Notch signaling contributes to the pathogenesis of human and murine OS, and its inhibition may be a therapeutic approach for the treatment of OS. As the multifunctional nuclear complex of Notch1 is essential for its oncogenic function, identifying these interacting partners represents a potentially broad range of druggable vulnerabilities. We have completed a BioID proteomics study and found a large set of nuclear proteins associated with Notch1, including transcriptional regulators and epigenetic modulators, of which HDAC1 is a promising interacting partner of Notch1. We performed proximity ligation assay (PLA) and showed their nuclear interaction in human OS cells. Our Cytoscape analysis predicted HDAC1 to be a critical node in an activated Notch state. We then assessed the influence of HDAC1 regulation of Notch signaling using a class 1 histone deacetylase inhibitor, 4SC-202, on the SJSA-1 osteosarcoma cell line. Our data showed that at 24-72hrs, 1uM of 4SC-202 significantly affected the proliferation of SJSA-1 cells. Similarly, we found an inhibitory effect on its colony formation abilities with 1uM of 4SC-202. A cell cycle flow analysis with propidium iodide indicates that there is a G2/M arrest upon 4SC-202 treatment, which is consistent with an observed decrease in wound healing capabilities of SJSA-1 in a scratch assay. Additionally, we found a significant decrease in SJSA-1 ability to migrate through a Transwell and also invade into Matrigel coated Transwell inserts in 24hrs. Under osteoblast differentiation conditions, 4SC-202 promotes SJSA-1 capacity to differentiate into osteoblasts, while SJSA-1 adipocyte differentiation capacity did not change. Western blot analysis indicates there is an increase in H3K27Ac protein expression and a decre