Long non-coding RNA HOTAIR promotes breast cancer progression and metastasis, induces ferroptosis by regulating the miR-206/CERS2 axis

Abstract Background: Ferroptosis, a novel form of regulated cell death induced by iron-dependent lipid peroxidation, plays an essential role in tumor development and drug resistance. Long non-coding RNA (lncRNA) HOX transcript antisense RNA (HOTAIR) has been reported to regulate the cell cycle, proliferation, apoptosis, and migration of tumor cells. However, the function and molecular mechanism of HOTAIR in regulating ferroptosis in tumors remain unclear. Methods: In this study, we analyzed transcriptome data from TCGA and FerrDb databases using R 4.3.1 and constructed a ceRNA network using Cytoscape 3.9.0. And investigate the effects of HOTAIR on breast cancer cells' proliferation, migration, invasion and ferroptosis through loss-of-function and gain experiments. We used subcellular localization prediction of genes, RNA immunoprecipitation assays, bioinformatics databases as well as RT-qPCR to elucidate the underlying mechanism of HOTAIR-induced competitive endogenous RNA regulatory network. Results: The functional tests showed that high expression levels of HOTAIR can promote breast cancer cell lines' proliferation, migration and invasion; thus it can be considered a pro-cancer regulator for breast cancer progression. Moreover, HOTAIR is highly expressed in breast cancer cell lines compared with normal tissues; patients exhibiting high HOTAIR expression have advanced clinical stages with numerous lymph node metastases leading to poor overall survival rates. Considering BRCA patients' clinical findings being insensitive to chemotherapy or immunotherapy, ferroptosis induction may be a promising therapeutic strategy for BRCA patients with high expression level of HOTAIR. Conclusions: Mechanistically, HOTAIR competitively interacts with miR-206 to up-regulate CERS2's expression participating in regulating ferroptosis in breast cancer cells.