lncRNA CYTOR promotes aberrant glycolysis and mitochondrial respiration via HNRNPC-mediated ZEB1 stabilization in oral squamous cell carcinoma

Oral squamous cell carcinoma (OSCC), the most common malignancy of the oral and maxillofacial region, severely affects human health. However, current treatments for OSCC commonly show only a ~60% five-year survival rate of patients with distant metastases, indicating an urgent need for targeted treatments for patients with advanced metastases. Here, we report a survival-related long non-coding RNA, CYTOR, which is highly expressed in the lesions of oral cancer patients. We found that CYTOR can promote both migration and invasion in oral cancer cells as well as the epithelial-mesenchymal transition (EMT). RNA-sequencing of CYTOR-knockdown oral cancer cells revealed that CYTOR can regulate mitochondrial respiration and RNA splicing. Mechanistically, we found that nuclear-localized CYTOR interacts with HNRNPC, resulting in stabilization of ZEB1 mRNAs by inhibiting the nondegradative ubiquitination of HNRNPC. By synthesizing CYTOR-targeting small interfering RNAs (siRNAs) encapsulated in Nanoscale Metal Organic Frameworks (NMOFs), we demonstrate the targeted suppression of CYTOR to inhibit invasion and metastasis of oral cancer cells in a nude mouse model. Cumulatively, this study reveals the potential role of the CYTOR-HNRNPC-ZEB1 axis in regulating mitochondrial metabolism and glycolysis of oral cancer cells, and illustrates the effective use of lncRNA targeting in anti-metastatic cancer therapies. For RNA-seq assays: (1) Cal27 cells were transfected by CYTOR-sh and negative control (NC) sequence to knockdown (KD) CYTOR expression level, three NC transfected samples and three CYTOR-KD transfected samples were analyszed. (2) Cal27 cells were transfected by HNRNPC-sh and negative control (NC) sequence to knockdown (KD) HNRNPC expression level, three NC transfected samples and three HNRNPC-KD transfected samples were analyszed. For RIP-seq assay: Cal27 cells were harvested by RIP lysis buffer, then the lysates were immunoprecipitated by 5μg anti-HNRNPC antibody. The purified input and HNRNPC-IP RNA samples were then subjected to RNA-seq analysis.