Positive Feedback Regulation of Circular RNA Hsa_circ_0000566 and HIF-1α promotes Osteosarcoma Progression and Glycolysis Metabolism

Abstract

Hypoxia is an indispensable factor for cancer progression and is closely associated with the Warburg effect. Circular RNAs (CircRNA) have garnered considerable attention in molecular malignancy therapy as they are potentially important modulators. However, the roles of circRNAs and hypoxia in osteosarcoma (OS) progression have not yet been elucidated. This study reveals the hypoxia-sensitive circRNA, Hsa_circ_0000566, that plays a crucial role in OS progression and energy metabolism under hypoxic stress. Hsa_circ_0000566 is regulated by hypoxia-inducible factor-1α (HIF-1α) and directly binds to it as well as to the Von Hippel-Lindau (VHL) E3 ubiquitin ligase protein. Consequentially, binding between VHL and HIF-1α is impeded. Furthermore, Hsa_circ_0000566 contributes to OS progression by binding to HIF-1α (while competing with VHL) and by confers protection against HIF-1α against VHL-mediated ubiquitin degradation. These findings demonstrate the existence of a positive feedback loop formed by HIF-1α and Hsa_circ_0000566 and the key role they play in OS glycolysis. Taken together, these data indicate the significance of Hsa_circ_0000566 in the Warburg effect and suggest that Hsa_circ_0000566 could be a potential therapeutic target to combat OS progression.

Hypoxia inducible factor-1ɑ as a potential therapeutic target for osteosarcoma metastasis

“…In the process of OS metastasis ( Figure 6 ), Hsa-circ-0000566 is regulated by HIF-1α, and both directly binds to VHLE3 ubiquitin ligase protein to inhibit VHL-mediated ubiquitin degradation, thereby promoting their pivotal role in glycolysis of OS cells ( Shen et al, 2023 ). Mechanistically, protein arginine methyltransferase 9 (PrMT9) exerts control over HIF-1α through a distinct mechanism.…”

Modulation of NLRP3 inflammasome-related-inflammation via RIPK1/RIPK3-DRP1 or HIF-1α signaling by phenothiazine in hypothermic and normothermic neuroprotection after acute ischemic stroke

“…Moreover, RIPK1 inhibitor reduced caspase-9-mediated apoptosis after rhabdomyolysis in rats [ 19 ]. In addition, hypoxia inducible factor 1-α (HIF-1α) is involved in regulation of biological functions such as inflammation and apoptosis which play a detrimental role in nervous system disorders [ 20 , 21 ]. HIF-1α exhibited an inflammation amplification effect [ 22 ].…”

circELP2 reverse‐splicing biogenesis and function as a pro‐fibrogenic factor by targeting mitochondrial quality control pathway

“…By screening the circRNAs that take part in cell growth, scholars found that the most of circRNAs not only play generic housekeeping roles but rather function in a regulatory and cell/tissue‐type‐specific manner 8 . Therefore, following the development of biotechnology, finding and analysing circRNAs has important clinical application value for drug action targets, gene therapy drugs or diagnostic biomarkers 9–11 …”

“… 8 Therefore, following the development of biotechnology, finding and analysing circRNAs has important clinical application value for drug action targets, gene therapy drugs or diagnostic biomarkers. 9 , 10 , 11 …”

“…8 Therefore, following the development of biotechnology, finding and analysing circRNAs has important clinical application value for drug action targets, gene therapy drugs or diagnostic biomarkers. [9][10][11] In our previous study, the dramatically dysfunctional cir-cRNAs were screened out from the plasma of IPF patients via circRNA microarray analysis. 12 Zhao group once has selected circANKRD42, circGRHPR, circCDC27, circZMYM2, circARH-GAP26 and circTADA2A to prove our data.…”