Abstract PO-044: Epigenetic silencing of SLC17A7 promotes osteosarcoma growth

Abstract

Abstract Osteosarcoma is an orphan disease with only 900 patients diagnosed each year in US. Most patients are adolescents with small number of older patients. The 5-survival rates for those with metastatic disease is only 30%. Frustratingly, there has been little change in treatment options (chemotherapy, surgery and radiotherapy) due to the difficulty of conducting clinical trials in this rare but deadly cancer. To address this, strong pre-clinical trial information is required to motivate clinical trial design. In vitro and in vivo, we identified that the pan-HDAC inhibitor, panobinostat is highly effective in limiting osteosarcoma growth and metastasis. Panobinostat is approved for the treatment of other malignancies but has noted toxicities. Therefore, to identify therapeutic targets, we explored the HDACs responsible for driving osteosarcoma metastasis and the specific genes through which those HDACs mediated their effects. Our data shows that HDAC1 and HDAC2 are key for osteosarcoma survival using siRNA approaches. Use of the HDAC1/2 selective inhibitor romidepsin in vitro and in vivo supported this finding. To identify targets being regulated by HDAC1/2, we performed microarray and proteomics analyses on romidepsin treated osteosarcoma cells. We found and validated independently that, SLC17A7, a metabolic vesicular glutamate transporter to be highly induced in response to romidepsin treatment; >100 fold more than base line in multiple osteosarcoma cell lines. Functionally, SLC17A7 allows entry of glutamate into the synaptic vesicles from cytoplasm and releases the glutamate from the cells via exocytosis. In our studies, we have seen that romidepsin treatment leads to reduced glutamate levels in the conditioned media and cell death indicating key roles for SLC17A7 in driving osteosarcoma progression and metastasis. In conclusion, our data shows that HDAC1/2 suppression of SLC17A7 is a novel means of promoting osteosarcoma progression and metastasis. Citation Format: Niveditha Nerlakanti, Jeremy McGuire, Diana Yu, Damon R. Reed, Conor C. Lynch. Epigenetic silencing of SLC17A7 promotes osteosarcoma growth [abstract]. In: Abstracts: AACR Special Virtual Conference on Epigenetics and Metabolism; October 15-16, 2020; 2020 Oct 15-16. Philadelphia (PA): AACR; Cancer Res 2020;80(23 Suppl):Abstract nr PO-044.