Abstract 4274: RNA methylation regulates osteosarcoma growth and progression via autophagy

Abstract

Abstract Osteosarcoma (OS) is the most common primary bone tumor and third most common cancer in children/teens, after lymphomas and brain tumors. OS is treated by surgery and multi-modal chemotherapy. Even though this treatment regimen has improved the 5-year survival rate to 60-70%, once osteosarcoma metastasize to lung and other bones, the survival is significantly reduced. Moreover, the quality of life for patients who do survive is often substantially reduced due to the toxicity associated with the chemotherapy. Since several decades, there hasn’t been any improvement in the osteosarcoma treatment outcome. Therefore, it is important to understand the molecular mechanism of osteosarcoma growth and metastasis and an urgent need to develop effective drug, which can be safe and effective for treating OS patients. We discovered that RNA methylation may regulate OS growth and progression by affecting autophagy. Our studies revealed that RNA demethylase AlkB homolog 5 (ALKBH5) supports OS viability, migration and invasion as well as tumor growth. We discovered several autophagy related genes were significantly altered in ALKBH5-silenced OS cells compared to scrambled control. Importantly, levels of LC3, which is a universal marker for monitoring autophagy, was significantly increased in ALKBH5 depleted OS cells. Furthermore, we found that autophagy initiation complex protein ULK1 level was drastically increased in ALKBH5-silenced cells when compared to scrambled control. To further establish the role of autophagy in osteosarcomogenesis, we treated OS cells with chloroquine, which is a well-known autophagy inhibitor and is currently being investigated for treating adult cancers in clinical trials. Interestingly, silencing of ALKBH5 significantly improved the efficacy of chloroquine as revealed by drastically reduced viability and invasive ability of OS cells. In conclusion, our study is first to shows that RNA methylation plays a critical role osteosarcoma growth and progression by regulating autophagy. Citation Format: Panneerdoss Subbarayalu, Pooja Yadav, Manjeet Rao. RNA methylation regulates osteosarcoma growth and progression via autophagy [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr 4274.