CircECE1 activates energy metabolism in osteosarcoma by stabilizing c-Myc

Abstract

Background Osteosarcoma (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. Methods The 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. Results We 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. Conclusions CircECE1 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.

Circular RNA circRHOBTB3 represses metastasis by regulating the HuR-mediated mRNA stability of PTBP1 in colorectal cancer

“…In addition, circRNAs function through interactions with a variety of RBPs. The patterns of circRNA-protein interactions include (i) protein scaffolds, in which circRNAs facilitate colocalization and complex formation between enzymes (such as phosphatases, transmethylases and ubiquitin ligases) and their substrates 14 , 15 ; (ii) protein recruiters, in which specific circRNAs may recruit proteins to certain cellular locations 16 , 17 ; (iii) protein function enhancers, in which individual circRNAs bind to and promote the functions of proteins 18 ; and (iv) protein sponges or decoys, in which circRNAs and other molecules with shared RBP binding motifs compete for binding with specific RBPs 19 , 20 . For instance, circACC1 functions as a protein scaffold to improve the enzymatic activity of the AMP-activated protein kinase (AMPK) holoenzyme by directly binding to the AMPK β and γ subunits, acting as a tumor promoter in CRC 14 .…”

Construction of a circRNA-miRNA-mRNA network based on competitive endogenous RNA reveals the key pathways and central genes of osteosarcoma in vivo

“…Although the combined application of surgery, chemotherapy, and radiotherapy signi cantly improves the survival rate of patients with OS, their prognosis is still very poor [3] . Related studies have described the functional mechanisms of some circRNA in OS [24,25] , but the potential functions and complex mechanisms of most circRNAs in OS have not been fully elucidated.…”

Circular RNAs Regulate Glucose Metabolism in Cancer Cells

“…TXNIP is an effective negative regulator of glucose uptake and aerobic glycolysis. 81 Shen et al 82 found that mRNA and protein expression levels of TXMP were significantly elevated in osteosarcoma cells with circECE1 knock out when compared to control cells. This indicates that TXNIP is mainly regulated by circECE1 transcription.…”