RBM15 m6A modification-mediated OTUB2 upregulation promotes cervical cancer progression via the AKT/mTOR signaling

Cervical cancer (CC) is a deadly gynecological tumor worldwide. Otubain 2 (OTUB2) has been recently identified as an oncogene in human malignancies. However, its expression and function remain unclear. This work aims to explore the role of OTUB2 in CC progression. Herein, The Cancer Genome Atlas data revealed that OTUB2 expression was significantly upregulated in cervical squamous cell carcinoma and endocervical adenocarcinoma (CESC) and gradually increased with CESC progression; moreover, OTUB2 expression predicted poor outcomes of CESC patients. Then, RT-qPCR and Western blotting were applied to determine mRNA and protein expression in CC and normal cells. Our results confirmed that OTUB2 was highly expressed in CC cell lines. As indicated by CCK-8, Transwell, and flow cytometry results, OTUB2 silencing attenuated proliferative and metastatic capacities of CC cells but promoted CC cell apoptosis. Then, RBM15, an N6-methyladenosine (m(6)A) methyltransferase writer, was also demonstrated to be upregulated in CESC and CC cells. Mechanistically, m(6)A RNA immunoprecipitation (Me-RIP) results showed that RBM15 inhibition reduced the m(6)A methylation level of OTUB2 in CC cells, leading to the decline of OTUB2 expression. In addition, OTUB2 inhibition deactivated the AKT/mTOR signaling in CC cells. Furthermore, SC-79 (AKT/mTOR activator) partially abated the inhibitory effects of OTUB2 knockdown on the AKT/mTOR signaling pathway and the malignant phenotypes of CC cells. In summary, this work showed that RBM15-mediated m(6)A modification led to OTUB2 upregulation, thereby promoting malignant behaviors of CC cells via the AKT/mTOR signaling pathway.

Automated summary

This study found that OTUB2 expression was significantly upregulated in cervical squamous cell carcinoma and endocervical adenocarcinoma, and its silence attenuated the proliferative and metastatic capacities of CC cells while promoting cell apoptosis. RBM15 was also demonstrated to be upregulated in CC cells and played a role in OTUB2 upregulation through m(6)A modification, thereby promoting malignant behaviors of CC cells via the AKT/mTOR signaling pathway.