Abstract
BackgroundOsteosarcoma (OS) is the most common malignant bone tumor and has a poor prognosis. The potential involvement of circular RNAs (circRNAs) in OS progression remains unexplored.Here, we report that CircECE1, a circular RNA derived from human ECE1, plays a critical role in energy metabolism in OS.MethodsThe RIP chip sequence assay was performed to confirm CircECE1, through overexpression or knockdown of CircECE1 to verify its function in 143B and U2OS. RNA immunoprecipitation and immunoprecipitation were used to verify CircECE1’s regulation of protein c-Myc and co- immunoprecipitation was used to verified the competitive binding relationship between CircECE1 and SPOP. The influence of CircECE1 on energy metabolism was evaluated by seahorse experiment, western blot, and immunohistochemistry.ResultsWe found that CircECE1 is highly expressed in OS tissues and cells and that CircECE1 knockdown suppresses tumor proliferation and metastasis both in vitro and in vivo. Further, CircECE1 significantly promotes glucose metabolism in OS cells in vitro and in vivo. Mechanistically, CircECE1 interacts with c-Myc to prevent speckle-type POZ-mediated c-Myc ubiquitination and degradation. C-Myc inhibits thioredoxin binding protein (TXNIP) transcription and subsequently activates the Warburg effect.ConclusionsCircECE1 regulates the Warburg effect through the c-Myc/TXNIP axis. CircECE1 mediated signal transduction plays a important role in OS process and energy metabolism. These findings may identify novel targets for OS molecular therapy.
Highlights
Osteosarcoma (OS) is the most common malignant bone tumor and has a poor prognosis
These findings reveal that CircECE1 is overexpressed in OS
To validate the effect of CircECE1 in mediating c-Myc function, we investigated whether c-Myc knockdown could reverse the changes in target genes induced by CircECE1 overexpression. c-Myc knockdown blocked the upregulation of JunB, Mdm2, HIF1α, c-Jun, ELK-1, and Cdc25a that was induced by CircECE1 overexpression (Fig. 2i)
Summary
Osteosarcoma (OS) is the most common malignant bone tumor and has a poor prognosis. OS is most common during childhood and adolescence [1, 2] It is characterized by direct formation of osteoid tissue and uncontrolled proliferation of bone-related mesenchymal cells and is highly aggressive; 75% of OS cases have invasion of nearby tissues [2, 3]. With the development of RNA high-throughput sequencing technology and advances in biotechnology, many noncoding RNAs have been found to perform a variety of biological functions in the human body and to participate in the occurrence and development of tumors and other diseases. Circular RNAs (circRNAs), an enigmatic subclass of endogenous long noncoding RNAs that regulate genes at the transcriptional or
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