Hypoxia drives cervical cancer progression via OCT4/ORAI3-dependent glycolysis and Ca2+ signaling

Cervical cancer is a common cancer among women worldwide. It has been revealed that hypoxia contributes to the progression of cervical cancer. In our study, we discovered that hypoxia indeed promoted the malignant phenotypes of cervical cancer cells by enhancing glycolysis. Loss-of-function experiments showed that hypoxia treatment upregulated the octamer-binding transcriptional factor 4 (OCT4) expression via glycolysis. Through the RNA-sequence and enrichment analyses, we found that hypoxia induced the enrichment of the calcium signaling pathway and upregulation of Calcium Release-Activated Calcium Modulator 3 (ORAI3), which could be abrogated by silencing OCT4. Notably, overexpressing ORAI3 has similar effects on the malignant phenotypes of HeLa and SiHa cells as those of hypoxia. Furthermore, silencing ORAI3 or inactivating calcium signals significantly reversed OCT4-induced malignant progression of cervical cancer both in vitro and in vivo. ChIP and dual-luciferase reporter results confirmed that OCT4 contributed to the transcription of ORAI3. Mechanically, hypoxia upregulated OCT4 expression by facilitating glycolysis, and OCT4 overexpression enhanced the transcription of ORAI3, activating the calcium signaling pathway and ultimately promoting the malignant progression of cervical cancer. Our study reveals novel molecular mechanisms by which hypoxia induces the progression of cervical cancer, providing a new strategy for treating cervical cancer.