LncRNA HCP5-Encoded Protein Regulates Ferroptosis to Promote the Progression of Triple-Negative Breast Cancer

SIMPLE SUMMARY: The objective of the study was to investigate the possibility of lncRNA HCP5-encoded peptide/protein and the role of the resulting product in triple-negative breast cancer. Our study revealed that lncRNA HCP5 encodes a 132-amino acid sequence, referred to as HCP5-132aa, which enhances the growth of triple-negative breast cancer cells by regulating ferroptosis. Moreover, breast cancer patients with elevated levels of HCP5-132aa had a worse prognosis. Our findings have revealed a regulatory mechanism of ferroptosis in triple-negative breast cancer that is modulated by an lncRNA-encoded product. ABSTRACT: Background: Long non-coding RNAs (lncRNAs) are a class of RNA molecules that are longer than 200 nucleotides and were initially believed to lack encoding capability. However, recent research has found open reading frames (ORFs) within lncRNAs, suggesting that they may have coding capacity. Despite this discovery, the mechanisms by which lncRNA-encoded products are involved in cancer are not well understood. The current study aims to investigate whether lncRNA HCP5-encoded products promote triple-negative breast cancer (TNBC) by regulating ferroptosis. Methods: We used bioinformatics to predict the coding capacity of lncRNA HCP5 and conducted molecular biology experiments and a xenograft assay in nude mice to investigate the mechanism of its encoded products. We also evaluated the expression of the HCP5-encoded products in a breast cancer tissue microarray. Results: Our analysis revealed that the ORF in lncRNA HCP5 can encode a protein with 132-amino acid (aa), which we named HCP5-132aa. Further experiments showed that HCP5-132aa promotes TNBC growth by regulating GPX4 expression and lipid ROS level through the ferroptosis pathway. Additionally, we found that the breast cancer patients with high levels of HCP5-132aa have poorer prognosis. Conclusions: Our study suggests that overexpression of lncRNA HCP5-encoded protein is a critical oncogenic event in TNBC, as it regulates ferroptosis. These findings could provide new therapeutic targets for the treatment of TNBC.