Identification of a Micropeptide Linked to Cancer Stem Cell Regulation and Chemoresistance

Short open reading frames encoding micropeptides (miPEPs) less than 100 amino acids in length have recently emerged as important regulators of diverse biological functions. However, the functional role of cancer-specific miPEPs in cancer progression and therapeutic response remains largely unexplored. Genome-wide association studies have identified an association of Iroquois (IRX) clusters with multiple cancer risk. In this study, we identified 17 miPEPs generated from IRX clusters in prostate, breast, endometrial, and ovarian cancers using SWATH-MS/MS-based proteomic analysis. We found that IRX4-derived miPEP, IRX4_PEP1, promotes prostate cancer (PCa) cell proliferation, migration, and invasion by interacting with heterogeneous nuclear ribonucleoprotein K (hnRNPK). Overexpression of IRX4_PEP1 leads to dysregulation of stem cell pathways by co-interaction with Catenin beta-1 (CTNB1) and upregulation of prominent PCa stem markers, resulting in docetaxel resistance in PCa. IRX4_PEP1 expression is significantly upregulated in prostate tumour tissues compared to normal and is positively correlated with disease aggressiveness. SIGNIFICANCEOur findings highlight the critical role of IRX4_PEP1 in regulating PCa stem cells and chemotherapy resistance and suggest it as a novel therapeutic target for the treatment of PCa. Moreover, IRX4_PEP1 expression can serve as a novel potential diagnostic and prognostic biomarker for PCa.