The YTHDC1/HECW1/SMAD7 axis drives cisplatin resistance in bladder cancer

Background: Cisplatin-based combination chemotherapy remains the cornerstone of treatment for advanced bladder cancer (BC). However, primary or acquired resistance following long-term use remains a critical unresolved issue in BC treatment. While accumulating evidence implicates epitranscriptomic modifications in driving chemoresistance, the precise underlying mechanisms remain incompletely elucidated. Exploring the potential mechanisms underlying cisplatin resistance in BC is crucial for identifying novel therapeutic targets and prolonging patient survival. This study aims to identify the key N6-methyladenosine (m6A) regulatory factors related to chemotherapy resistance in BC and elucidate the underlying molecular mechanisms. Methods: Integrated bioinformatic analyses were performed to screen and identify critical m6A readers associated with cisplatin resistance in BC. Gene expression and molecular interactions were analyzed using reverse transcription-quantitative polymerase chain reaction (RT-qPCR), Western blotting, RNA immunoprecipitation (RIP), and co-immunoprecipitation. Cell proliferation and apoptosis assays were employed to evaluate chemosensitivity and therapeutic interventions. Results: In this study, we identified the m6A reader YTHDC1 as a critical regulator of cisplatin resistance in BC. Mechanistically, YTHDC1 expression was significantly downregulated in cisplatin-resistant BC cells. The reduced YTHDC1 expression enhanced the stability and inhibited the degradation of HECW1 messenger RNA (mRNA). Consequently, the upregulated E3 ubiquitin ligase HECW1 directly interacted with SMAD7 and promoted its ubiquitin-dependent proteasomal degradation. The diminished SMAD7 protein levels ultimately reduced the sensitivity of BC cells to cisplatin treatment. Conclusions: This study identifies a YTHDC1-HECW1-SMAD7 axis that regulates cisplatin resistance in BC. Targeting this axis with HDAC2 inhibitors or curcumin potentiates the anti-tumor efficacy of cisplatin, offering a promising therapeutic strategy to overcome chemoresistance in BC.