BIRC5 facilitates cisplatin‐chemoresistance in a m⁶A‐dependent manner in ovarian cancer

Abstract

Cisplatin‐based chemotherapy is the standard treatment for metastatic ovarian cancer (OC). However, chemoresistance continues to pose significant clinical challenges. Recent research has highlighted the baculoviral inhibitor of the apoptosis protein repeat‐containing 5 (BIRC5) as a member of the inhibitor of the apoptosis protein (IAP) family. Notably, BIRC5, which has robust anti‐apoptotic capabilities, is overexpressed in numerous cancers. Its dysfunction has been linked to challenges in cancer treatment. Yet, the role of BIRC5 in the chemoresistance of OC remains elusive. In our present study, we observed an upregulation of BIRC5 in cisplatin‐resistant cell lines. This upregulation was associated with enhanced chemoresistance, which was diminished when the expression of BIRC5 was silenced. Intriguingly, BIRC5 exhibited a high number of N6‐methyladenosine (m6A) binding sites. The modification of m6A was found to enhance the expression of BIRC5 by recognizing and binding to the 3′‐UTR of mRNA. Additionally, the insulin‐like growth factor 2 mRNA‐binding protein 1 (IGF2BP1) was shown to stabilize BIRC5 mRNA, synergizing with METTL3 and intensifying chemoresistance. Supporting these in vitro findings, our in vivo experiments revealed that tumors were significantly smaller in size and volume when BIRC5 was silenced. This reduction was notably counteracted by co‐silencing BIRC5 and overexpressing IGF2BP1. Our results underscored the pivotal role of BIRC5 in chemoresistance. The regulation of its expression and the stability of its mRNA were influenced by m6A modifications involving both METTL3 and IGF2BP1. These insights presented BIRC5 as a promising potential therapeutic target for addressing cisplatin resistance in OC.

Emerging role of m6A modification in ovarian cancer: progression, drug resistance, and therapeutic prospects

“…The overexpressed BIRC5 promotes cisplatin resistant in OC. Mechanistic study shows METTL3/IGF2BP1 promotes BIRC5 mRNA to confer cisplatin resistance in OC ( 124 ). The TRIM29 was overexpressed in cisplatin-resistant OC and enhanced the CSC like phenotype in cisplatin resistant OC.…”

“…PARPi FTO/ALKBH5-FZD10(Wnt/b-catenin signaling pathway) (124). The TRIM29 was overexpressed in cisplatin-resistant OC and enhanced the CSC like phenotype in cisplatin resistant OC.…”