Background: Osteosarcomas (OS) are frequent primary sarcomas of the bone in children and adolescents. The long non-coding RNAs (lncRNAs) can affect the progression of many cancers by their sense transcripts. The present study was designed to probe the role of ZMIZ1-AS1 and the downstream pathway in OS progression.
Methods: Cell proliferation, invasion, and migration were detected by colony formation, transwell, and wound healing assays. The binding of SOX2 or MYC protein with ZMIZ1-AS1 promoter was explored by ChIP assay and dual-luciferase reporter assay. Interaction between PTBP1 protein and ZMIZ1-AS1 (or ZMIZ1 mRNA) was detected by RIP assay.
Results: SOX2 and MYC are the downstream effectors of the Hippo pathway and transcriptionally activated ZMIZ1-AS1. Compared to the controls, OS tissues and cells contained higher ZMIZ1-AS1 expression. Silencing of ZMIZ1-AS1 repressed OS cell viability, proliferation, migration, and invasion. Our findings further showed that ZMIZ1-AS1 recruits RNA-binding protein PTBP1 to stabilize ZMIZ1 mRNA. PTBP1 or ZMIZ1 overexpression rescues the suppressive effects of silenced ZMIZ1-AS1 on OS cellular processes. Importantly, ZMIZ1-AS1 promotes OS growth in vivo by stabilization of ZMIZ1.
Conclusions: Long non-coding RNA ZMIZ1-AS1 promotes OS progression by stabilization of ZMIZ1. The Hippo pathway is inactivated in osteosarcoma. Transcriptional factors SOX2 and MYC downstream the Hippo pathway induce the upregulation of ZMIZ1-AS1 in osteosarcoma. ZMIZ1-AS1 recruits RNA binding protein PTBP1 that stabilizes ZMIZ1, the sense transcript of ZMIZ1-AS1. ZMIZ1-AS1 promotes osteosarcoma cell viability, proliferation, migration, and invasion by ZMIZ1 in a PTBP1 dependent manner.
Keywords: MYC; Osteosarcoma; PTBP1; SOX2; ZMIZ1; ZMIZ1-AS1; the Hippo pathway.
© 2021. The Author(s), under exclusive licence to Springer Nature B.V.